Novel benzimidazole derivatives useful as selective androgen receptor modulators (sarms)

ABSTRACT

The present invention is directed to novel benzimidazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/614,707, filed on Sep. 30, 2004, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel benzimidazole derivatives,pharmaceutical compositions containing them and their use in thetreatment of disorders and conditions modulated by the androgenreceptor. More particularly, the compounds of the present invention areuseful in the treatment of prostate carcinoma, benign prostatichyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer,acne, AIDS, cachexia, as a male contraceptive, and/or as a maleperformance enhancer.

BACKGROUND OF THE INVENTION

Androgens are the anabolic steroid hormones of animals, controllingmuscle and skeletal mass, the maturation of the reproductive system, thedevelopment of secondary sexual characteristics and the maintenance offertility in the male. In women, testosterone is converted to estrogenin most target tissues, but androgens themselves may play a role innormal female physiology, for example, in the brain. The chief androgenfound in serum is testosterone, and this is the effective compound intissues such as the testes and pituitary. In prostate and skin,testosterone is converted to dihydrotestosterone (DHT) by the action of5α-reductase. DHT is a more potent androgen than testosterone because itbinds more strongly to the androgen receptor.

Like all steroid hormones, androgens bind to a specific receptor insidethe cells of target tissues, in this case the androgen receptor. This isa member of the nuclear receptor transcription factor family. Binding ofandrogen to the receptor activates it and causes it to bind to DNAbinding sites adjacent to target genes. From there it interacts withcoactivator proteins and basic transcription factors to regulate theexpression of the gene. Thus, via its receptor, androgens cause changesin gene expression in cells. These changes ultimately have consequenceson the metabolic output, differentiation or proliferation of the cellthat are visible in the physiology of the target tissue.

Although modulators of androgen receptor function have been employedclinically for some time, both the steroidal (Basaria, S., Wahlstrom, J.T., Dobs, A. S., J. Clin Endocrinol Metab (2001), 86, pp 5108-5117;Shahidi, N. T., Clin Therapeutics, (2001), 23, pp 1355-1390), andnon-steroidal (Newling, D. W., Br. J. Urol., 1996, 77 (6), pp 776-784)compounds have significant liabilities related to their pharmacologicalparameters, including gynecomastia, breast tenderness and hepatoxicity.In addition, drug-drug interactions have been observed in patientsreceiving anticoagulation therapy using coumarins. Finally, patientswith aniline sensitivities could be compromised by the metabolites ofnon-steroidal antiandrogens.

Non-steroidal agonists and antagonists of the androgen receptor areuseful in the treatment of a variety of disorders and diseases. Moreparticularly, agonists of the androgen receptor could be employed in thetreatment of prostate cancer, benign prostatic hyperplasia, hirsutism inwomen, alopecia, anorexia nervosa, breast cancer and acne. Antagonistsof the androgen receptor could be employed in male contraception, maleperformance enhancement, as well as in the treatment of cancer, AIDS,cachexia, and other disorders.

Nonetheless, there exists a need for small molecule, non-steroidalagonist and/or antagonists of the androgen receptor. We now describe anovel series of benzimidazole derivatives as androgen receptormodulators.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

R¹ is selected from the group consisting of hydrogen, C₁₋₄alkyl,—C₁₋₄alkyl-OH, —C₁₋₄alkyl-CN, —C₁₋₄alkyl-NO₂, —C₁₋₄alkyl-N(R^(A)R^(B)),—C₁₋₄alkyl-CO₂H, —(C₁₋₄alkyl)-X—R⁷, —CH₂-aryl and —CH₂-heteroaryl;wherein the aryl or heteroaryl group (on the —CH₂-aryl and—CH₂-heteroaryl group) is optionally substituted with one or moresubstituents independently selected from halogen, C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkoxy,—C₁₋₄alkyl-CN, —C₁₋₄alkyl-OH, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S—C₁₋₄alkyl, —S-(halogen substituted C₁₋₄alkyl),—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl, —O-aralkyl, —C(O)O—C₁₋₄alkyl, —CO₂H,—C(O)H, heteroaryl or heterocycloalkyl;

wherein R^(A) and R^(B) are independently selected from hydrogen orC₁₋₄alkyl; alternatively, R^(A) and R^(B) are taken together with thenitrogen atom to which they are bound to form a five to seven memberedaromatic, partially unsaturated or saturated ring structure, optionallycontaining one to two additional heteroatoms selected from O, S or N;and wherein the ring structure is optionally substituted with C₁₋₄alkyl;

wherein X is selected from the group consisting of —S—, —SO—, SO₂—,—O—SO₂—, —O—, —C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR^(C)—,—NR^(C)—C(O)—, —C(O)—NR^(C)—, —NR^(C)—SO₂— and —SO₂—NR^(C)—; whereinR^(C) is selected from hydrogen or C₁₋₄alkyl;

wherein R⁷ is selected from the group consisting of C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₂₋₄alkenyl, aryl, aralkyl, biphenyl, cycloalkyl,cycloalkyl-(C₁₋₄alkyl)-, heteroaryl, heteroaryl-(C₁₋₄alkyl)-,heterocycloalkyl and heterocycloalkyl-(C₁₋₄alkyl)-; wherein thecycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone oras part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S(O)₀₋₂—C₁₋₄alkyl), —SO₂—N(R^(D))₂, aryl,heteroaryl or heterocycloalkyl; wherein each R^(D) is independentlyselected from hydrogen or C₁₋₄alkyl;

provided that when X is O or NR^(C), then R⁶ is other than C₂₋₄alkenyl;

R² is selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano, nitro, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S—C₁₋₄alkyl,—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl and —NR^(E)—C(O)—C₁₋₄alkyl; wherein R^(E)is selected from hydrogen or C₁₋₄alkyl;

R³ is selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano, nitro, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S—C₁₋₄alkyl,—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl and —NR^(F)—C(O)—C₁₋₄alkyl; wherein R^(F)is selected from hydrogen or C₁₋₄alkyl;

provided that at least one of R² or R³ is other than hydrogen;

a is an integer from 0 to 1;

R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl and —C(O)—R⁸;

wherein R⁸ is selected from the group consisting of C₁₋₄alkyl,cycloalkyl, cycloalkyl-(C₁₋₄alkyl)-, aryl, aralkyl, heteroaryl,heteroaryl-(C₁₋₄alkyl)-, heterocycloalkyl andheterocycloalkyl-(C₁₋₄alkyl)-; wherein the alkyl, cycloalkyl, aryl,heteroaryl or heterocycloalkyl group, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino ordi(C₁₋₄alkyl)amino;

R⁵ is selected from the group consisting of hydrogen, halogen, C₁₋₄alkyland halogen substituted C₁₋₄alkyl;

R⁶ is selected from the group consisting of C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, —C₁₋₄alkyl-OH, —C₁₋₄alkyl-CN, —C₁₋₄alkyl-NO₂,—C₁₋₄alkyl-N(R^(G)R^(H)), C₁₋₄alkyl-CO₂H, —(C₁₋₄alkyl)-Y—R⁹, —CH₂-aryland —CH₂-heteroaryl; wherein the aryl or heteroaryl (on the —CH₂-aryl or—CH₂-heteroaryl group) is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, C₁₋₄alkyl,halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogen substitutedC₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,—S(O)₀₋₂—C₁₋₄alkyl or —SO₂—N(R^(J))₂; wherein each R^(J) isindependently selected from hydrogen or C₁₋₄alkyl;

wherein R^(G) and R^(H) are independently selected from hydrogen orC₁₋₄alkyl; alternatively, R^(G) and R^(H) are taken together with thenitrogen atom to which they are bound to form a five to seven memberedaromatic, partially unsaturated or saturated ring structure, optionallycontaining one to two additional heteroatoms selected from O, S or N;and wherein the ring structure is optionally substituted with C₁₋₄alkyl;

wherein Y is selected from the group consisting of —S—, —SO—, SO₂—,—O—SO₂—, —O—, —C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR^(K)—,—NR^(K)—C(O)—, —C(O)—NR^(K)—, —NR^(K)—SO₂— and —SO₂—NR^(K)—; whereinR^(K) is selected from hydrogen or C₁₋₄alkyl;

wherein R⁹ is selected from the group consisting of C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₂₋₄alkenyl, aryl, aralkyl, biphenyl, cycloalkyl,cycloalkyl-(C₁₋₄alkyl)-, heteroaryl, heteroaryl-(C₁₋₄alkyl)-,heterocycloalkyl and heterocycloalkyl-(C₁₋₄alkyl)-; wherein thecycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone oras part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S(O)₀₋₂—(C₁₋₄alkyl), —SO₂—N(R^(L))₂ or—NR^(M)—C(O)—C₁₋₄alkyl; wherein each R^(L) is independently selectedfrom hydrogen or C₁₋₄alkyl; and wherein R^(M) is selected from hydrogenor C₁₋₄alkyl;

provided that when Y is O or NR^(K), then R⁹ is other than C₂₋₄alkenyl;

provided that when R⁴ is hydrogen and R⁵ is hydrogen, then R⁶ is otherthan C₁₋₄alkyl;

provided further that when R¹ is hydrogen; a is 0; R⁴ is hydrogen and R⁵is C₁₋₄alkyl; then R⁶ is other than C₁₋₄alkyl;

provided further that when R¹ is hydrogen; a is 0; R² is —O—C₁₋₄alkyl;R³ is hydrogen; R⁴ is hydrogen; R⁵ is hydrogen; then R⁶ is other than—CH₂-phenyl, wherein the phenyl is substituted with —O—C₁₋₄alkyl;

provided further that when R¹ is hydrogen, a is 0, R⁴ is hydrogen and R⁵is hydrogen; then R⁶ is other than —CH₂— (benzimidazolyl), wherein thebenzimidazolyl is substituted with one to two substituents selected fromhalogen, C₁₋₄alkyl or —O—C₁₋₄alkyl;

or a pharmaceutically acceptable salt thereof.

The present invention is further directed to compounds of formula (II)

wherein

R¹ is selected from the group consisting of hydrogen, C₁₋₄alkyl,—C₁₋₄alkyl-OH, —C₁₋₄alkyl-CN, —C₁₋₄alkyl-NO₂, —C₁₋₄alkyl-N(R^(A)R^(B)),—C₁₋₄alkyl-CO₂H, —(C₁₋₄alkyl)-X—R⁷, —CH₂-aryl and —CH₂-heteroaryl;wherein the aryl or heteroaryl group (on the —CH₂-aryl and—CH₂-heteroaryl group) is optionally substituted with one or moresubstituents independently selected from halogen, C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkoxy,—C₁₋₄alkyl-CN, —C₁₋₄alkyl-OH, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S—C₁₋₄alkyl, —S-(halogen substituted C₁₋₄alkyl),—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl, —O-aralkyl, —C(O)O—C₁₋₄alkyl, —CO₂H,—C(O)H, heteroaryl or heterocycloalkyl;

wherein R^(A) and R^(B) are independently selected from hydrogen orC₁₋₄alkyl; alternatively, R^(A) and R^(B) are taken together with thenitrogen atom to which they are bound to form a five to seven memberedaromatic, partially unsaturated or saturated ring structure, optionallycontaining one to two additional heteroatoms selected from O, S or N;and wherein the ring structure is optionally substituted with C₁₋₄alkyl;

wherein X is selected from the group consisting of —S—, —SO—, SO₂—,—O—SO₂—, —O—, —C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR^(C)—,—NR^(C)—C(O)—, —C(O)—NR^(C)—, —NR^(C)—SO₂— and —SO₂—NR^(C)—; whereinR^(C) is selected from hydrogen or C₁₋₄alkyl;

wherein R⁷ is selected from the group consisting of C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₂₋₄alkenyl, aryl, aralkyl, biphenyl, cycloalkyl,cycloalkyl-(C₁₋₄alkyl)-, heteroaryl, heteroaryl-(C₁₋₄alkyl)-,heterocycloalkyl and heterocycloalkyl-(C₁₋₄alkyl)-; wherein thecycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone oras part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S(O)₀₋₂—(C₁₋₄alkyl), —SO₂—N(R^(D))₂, aryl,heteroaryl or heterocycloalkyl; wherein each R^(D) is independentlyselected from hydrogen or C₁₋₄alkyl;

provided that when X is O or NR^(C), then R⁶ is other than C₂₋₄alkenyl;

R² is selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano, nitro, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S—C₁₋₄alkyl,—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl and —NR^(E)—C(O)—C₁₋₄alkyl; wherein R^(E)is selected from hydrogen or C₁₋₄alkyl;

R³ is selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano, nitro, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S—C₁₋₄alkyl,—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl and —NR^(F)—C(O)—C₁₋₄alkyl; wherein R^(F)is selected from hydrogen or C₁₋₄alkyl;

provided that at least one of R² or R³ is other than hydrogen;

a is an integer from 0 to 1;

R¹⁰ is selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl and —O—C(O)—R⁸;

wherein R⁸ is selected from the group consisting of C₁₋₄alkyl,cycloalkyl, cycloalkyl-(C₁₋₄alkyl)-, aryl, aralkyl, heteroaryl,heteroaryl-(C₁₋₄alkyl)-, heterocycloalkyl andheterocycloalkyl-(C₁₋₄alkyl)-; wherein the alkyl, cycloalkyl, aryl,heteroaryl or heterocycloalkyl group, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino ordi(C₁₋₄alkyl)amino;

R¹¹ is selected from the group consisting of hydrogen and halogen;

alternatively, R¹⁰ and R¹¹ are taken together with the carbon atom towhich they are abound to form —C(O)—, C═N(OH) or —C═N(O—C₁₋₄alkyl);

R¹² is selected from the group consisting of C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, —C₁₋₄alkyl-OH, —C₁₋₄alkyl-CN, —C₁₋₄alkyl-NO₂,—C₁₋₄alkyl-N(R^(G)R^(H)), C₁₋₄alkyl-CO₂H, —(C₁₋₄alkyl)-Y—R⁹, —CH₂-aryland —CH₂-heteroaryl; wherein the aryl or heteroaryl (on the —CH₂-aryl or—CH₂-heteroaryl group) is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, C₁₋₄alkyl,halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogen substitutedC₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,—S(O)₀₋₂—C₁₋₄alkyl or —SO₂—N(R^(J))₂; wherein each R^(J) isindependently selected from hydrogen or C₁₋₄alkyl;

wherein R^(G) and R^(H) are independently selected from hydrogen orC₁₋₄alkyl; alternatively, R^(G) and R^(H) are taken together with thenitrogen atom to which they are bound to form a five to seven memberedaromatic, partially unsaturated or saturated ring structure, optionallycontaining one to two additional heteroatoms selected from O, S or N;and wherein the ring structure is optionally substituted with C₁₋₄alkyl;

wherein Y is selected from the group consisting of —S—, —SO—, SO₂—,—O—SO₂—, —O—, —C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR^(K)—,—NR^(K)—C(O)—, —C(O)—NR^(K)—, —NR^(K)—SO₂— and —SO₂—NR^(K)—; whereinR^(K) is selected from hydrogen or C₁₋₄alkyl;

wherein R⁹ is selected from the group consisting of C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₂₋₄alkenyl, aryl, aralkyl, biphenyl, cycloalkyl,cycloalkyl-(C₁₋₄alkyl)-, heteroaryl, heteroaryl-(C₁₋₄alkyl)-,heterocycloalkyl and heterocycloalkyl-(C₁₋₄alkyl)-; wherein thecycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone oras part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S(O)₀₋₂—(C₁₋₄alkyl), —SO₂—N(R^(L))₂ or—NR^(M)—C(O)—C₁₋₄alkyl; wherein each R^(L) is independently selectedfrom hydrogen or C₁₋₄alkyl; and wherein R^(M) is selected from hydrogenor C₁₋₄alkyl;

provided that when Y is O or NR^(K), then R⁹ is other than C₂₋₄alkenyl;

provided that when R¹ is —CH₂-phenyl wherein the phenyl is substitutedwith —C(O)O—C₁₋₄alkyl or —CO₂H; R² is methyl; R³ is methyl; a is 0; R¹⁰is hydrogen; and R¹¹ is hydrogen; then R¹² is other than —CH₂-phenyl;

provided further that when R¹ is —CH₂-phenyl wherein the phenyl issubstituted with —C(O)O—C₁₋₄alkyl or —CO₂H; R² and R³ are selected to be(H and fluoro), (fluoro and H), (methyl, methyl) or (H andtrifluoromethyl); a is an integer form 0 to 1; R¹⁰ is hydrogen; and R¹¹is hydrogen; then R¹² is other than C₁₋₄alkyl;

provided further that when R¹ is hydrogen or C₁₋₄alkyl; a is 0; R¹⁰ andR¹¹ are taken together with the carbon atom to which they are abound toform —C(O)—, one of R² or R³ is hydrogen and the other of R² or R³ isselected from halogen, C₁₋₄alkyl, —O—C₁₋₄alkyl or nitro, then R¹² isother than C₁₋₄alkyl, C₁₋₄alkyl substituted with one halogen or benzyl;

provided further that when R¹ is —CH₂-phenyl; a is 0; R¹⁰ and R¹¹ aretaken together with the carbon atom to which they are abound to form—C(O)—, of R² is hydrogen; and R³ is nitro, then R¹² is other thanC₁₋₄alkyl;

provided further that when R¹ is hydrogen; a is 0; R² is —O—C₁₋₄alkyl,R³ is —O—C₁₋₄alkyl; and R¹⁰ and R¹¹ are taken together with the carbonatom to which they are abound to form —C(O)—; then R¹² is other thanbenzyl;

provided further that when R¹ is —C₁₋₄alkyl-N(C₁₋₄alkyl)₂; a is 0; R² is—O—C₁₋₄alkyl; R³ is —O—C₁₋₄alkyl; and R¹⁰ and R¹¹ are taken togetherwith the carbon atom to which they are abound to form —C(O)—, then R¹²is other than benzyl, wherein the benzyl is substituted with a halogen;

or a pharmaceutically acceptable salt thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedherein. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described herein and a pharmaceutically acceptablecarrier.

Exemplifying the invention are methods of treating disorders andconditions modulated by the androgen receptor in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of any of the compounds or pharmaceutical compositionsdescribed herein.

An example of the invention is a method for treating an androgenreceptor modulated disorder selected from the group consisting ofprostate carcinoma, benign prostatic hyperplasia, hirsutism, or for malecontraception, in a subject in need thereof comprising administering tothe subject an effective amount of any of the compounds orpharmaceutical compositions described herein.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)prostate carcinoma, (b) benign prostatic hyperplasia, (c) hirsutism, (d)alopecia, (e) anorexia nervosa, (f) breast cancer, (g) acne, (h) AIDS,(i) cachexia, for (j) male contraception, or for (k) male performanceenhancement, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I) andcompounds of formula (II)

wherein R¹, R², R³, a, R⁴, R⁵, R⁶, R¹⁰, R¹¹ and R¹², are as hereindefined, useful as selective androgen receptor modulators for thetreatment of prostate carcinoma, benign prostatic hyperplasia (BPH),hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS,cachexia, as a male contraceptive, and/or as a male performanceenhancer. One skilled in the art will recognize that some compounds offormula (I) may be metabolites of the corresponding compounds of formula(II).

One skilled in the art will recognize that some of the variables (e.g.R¹, R², R³, a, etc.) appear in compounds of formula (I) and compounds offormula (II). One skilled in the art will further recognize that whereina particular substituent is selected for a given variable for a compoundof formula (I), said selection is not intended to limit the scope ofsaid variable for compounds of formula (II). Similarly, the selection ofa particular substituent for a given variable for a compound of formula(II), is not intended to limit the scope of said variable for compoundsof formula (I).

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —CH₂-phenyl and —CH₂-heteroaryl;wherein the phenyl or heteroaryl (on the —CH₂-phenyl or —CH₂-heteroarylgroup) is optionally substituted with one or more substituentsindependently selected from halogen, C₁₋₄alkyl, halogen substitutedC₁₋₄alkyl, —O-(halogen substituted C₁₋₄alkyl), nitro, cyano, —S-(halogensubstituted C₁₋₄alkyl), —SO₂—C₁₋₄alkyl, —O—CH₂-phenyl, —C(O)O—C₁₋₄alkyl,—C(O)H, heteroaryl or heterocycloalkyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, C₁₋₄alkyl, —C₁₋₄alkyl-OH, —C₁₋₄alkyl-CN,—C₁₋₄alkyl-X—R⁷, —CH₂-phenyl and —CH₂-heteroaryl; wherein the phenyl orheteroaryl (on the —CH₂-phenyl or —CH₂-heteroaryl group) is optionallysubstituted with one or more substituents independently selected fromhalogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,—O-(halogen substituted C₁₋₄alkyl), —C₁₋₄alkyl-CN, nitro, cyano,—S-(halogen substituted C₁₋₄alkyl), —SO₂—C₁₋₄alkyl, —O—CH₂-phenyl,—C(O)O—C₁₋₄alkyl, —C(O)H, heteroaryl or heterocycloalkyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, —C₁₋₄alkyl, —C₁₋₄alkyl-CN,—C₁₋₄alkyl-O—C₁₋₄alkyl and —C₁₋₄alkyl-S(O)₀₋₂—C₁₋₄alkyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, C₁₋₂alkyl, —C₁₋₂alkyl-OH, —C₁₋₂alkyl-CN,—C₁₋₂alkyl-O—C₁₋₂alkyl and —C₁₋₂alkyl-S(O)₀₋₂—C₁₋₂alkyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, —CH₂-heteroaryl and —C₁₋₂alkyl-X—R⁷.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, —CH₂-heteroaryl and —CH₂—C(O)-heteroaryl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl,cyano-methyl, methoxy-methyl and methyl-thio-methyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, methyl, 2-hydroxyethyl-,2-hydroxy-n-butyl-, cyano-methyl-, methoxy-methyl-, methyl-thio-methyl-,methyl-sulfonyl-methyl-, 4-chlorophenyl-sulfonyl-methyl-,ethoxy-carbonyl-methyl-, ethyl-carbonyl-methyl-,phenyl-carbonyl-methyl-, 4-fluorophenyl-carbonyl-methyl-,4-bromophenyl-carbonyl-methyl-, 4-chlorophenyl-carbonyl-methyl-,3-nitrophenyl-carbonyl-methyl-, 4-nitrophenyl-carbonyl-methyl-,2-methoxyphenyl-carbonyl-methyl-, 3-methoxyphenyl-carbonyl-methyl-,2,4-dimethoxyphenyl-carbonyl-methyl-, 2-benzofuryl-carbonyl-methyl-,2-thienyl-carbonyl-methyl-, 2-pyridyl-carbonyl-methyl-,3-pyridyl-carbonyl-methyl-, 2-(5-(2-pyridyl)-thienyl)-carbonyl-methyl-,5-(2,3-dihydrobenzo[1,4]dioxinyl)-carbonyl-methyl-,3-phenyl-5-methyl-isoxazol-4-yl-carbonyl-methyl-,4-fluorophenoxy-ethyl-, 4-chlorophenoxy-ethyl-, 3-fluorophenoxy-ethyl-,4-cyanophenoxy-ethyl-, 4-benzaldehyde, benzyl, 2-chlorobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 2-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,4-methoxybenzyl, 3-methylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, 3-trifluoromethoxybenzyl,4-trifluoromethoxybenzyl, 2,3,4,5,6-pentafluorobenzyl,2-cyanomethylbenzyl, 3-cyanomethylbenzyl, 2-methoxy-5-nitro-benzyl,4-cyanobenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl,4-trifluoromethyl-thio-benzyl, 4-methylsulfonyl-benzyl,4-benzyloxy-benzyl, 4-ethoxycarbonyl-benzyl, 4-pyrazolyl-benzyl,4-[1,2,3]-thiadiazol-4-yl-benzyl, 4-pyrrolyl-benzyl,3-(5-methyl-isoxazolyl)-methyl-, 2-pyridyl-methyl-, 3-pyridyl-methyl-,4-pyridyl-methyl- and trans-butan-2-one oxime.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen and methoxy-methyl-.

In another embodiment of the present invention, R¹ is hydrogen.

In an embodiment of the present invention, X is selected from the groupconsisting of —O—, S—, —SO—, —SO₂—, —C(O)—, —C(O)O— and —C(═N(OH))—.

In another embodiment of the present invention, X is selected from thegroup consisting of —O—, —S—, —SO₂— and —C(O)—.

In another embodiment of the present invention, X is selected from thegroup consisting of —O—, —S— and —SO₂—.

In an embodiment of the present invention, R⁷ is selected from the groupconsisting of C₁₋₄alkyl, phenyl, —CH₂-phenyl, heteroaryl andheterocycloalkyl; wherein the phenyl or heteroaryl, whether alone or aspart of a substituent group, is optionally substituted with one or moresubstituents independently selected from halogen, cyano, nitro,—C₁₋₄alkyl, —O—C₁₋₄alkyl, phenyl or heteroaryl.

In another embodiment of the present invention, R⁷ is selected from thegroup consisting of C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, phenyl,benzyl and heteroaryl; wherein the phenyl or heteroaryl is optionallysubstituted with one to two substituents independently selected fromhalogen, C₁₋₂alkyl, —O—C₁₋₂alkyl, halogen substituted C₁₋₂alkyl, nitroor cyano.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, halogen, C₁₋₄alkyl, halogen substitutedC₁₋₄alkyl, —O—C₁₋₄alkyl, cyano and nitro.

In another embodiment of the present invention, R² is selected from thegroup consisting of hydrogen, halogen, C₁₋₄alkyl, halogen substitutedC₁₋₄alkyl, —O—C₁₋₄alkyl and nitro.

In another embodiment of the present invention, R² is selected from thegroup consisting of halogen, —C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,—O—C₁₋₄alkyl, cyano and nitro.

In another embodiment of the present invention, R² is selected from thegroup consisting of halogen, C₁₋₄alkyl and halogen substitutedC₁₋₄alkyl.

In another embodiment of the present invention, R² is halogen.

In another embodiment of the present invention, R² is selected from thegroup consisting of hydrogen, chloro, fluoro, methyl, trifluoromethyl,methoxy and nitro.

In another embodiment of the present invention, R² is selected from thegroup consisting of chloro and trifluoromethyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of fluoro, chloro and methyl.

In an embodiment of the present invention, R³ is selected from the groupconsisting of hydrogen, halogen, C₁₋₄alkyl, halogen substitutedC₁₋₄alkyl, —O—C₁₋₄alkyl, cyano and nitro.

In another embodiment of the present invention, R³ is selected from thegroup consisting of halogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, cyano and nitro.

In another embodiment of the present invention, R³ is selected from thegroup consisting of halogen, —C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,—O—C₁₋₄-alkyl, cyano and nitro.

In another embodiment of the present invention, R³ is selected from thegroup consisting of halogen and cyano.

In another embodiment of the present invention, R³ is halogen.

In another embodiment of the present invention, R³ is selected from thegroup consisting of chloro, fluoro, methyl, methoxy, cyano and nitro.

In another embodiment of the present invention, R³ is selected from thegroup consisting of chloro and cyano.

In another embodiment of the present invention, R³ is chloro.

In an embodiment of the present invention R² is halogen and R³ ishalogen. In another embodiment of the present invention R² is chloro andR³ is chloro.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of hydrogen, C₁₋₄alkyl and

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and halogen substitutedC₁₋₄alkyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of hydrogen and C₁₋₄alkyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of hydrogen, methyl, ethyl and

In an embodiment of the present invention, R⁵ is selected from the groupconsisting of hydrogen, halogen and C₁₋₄alkyl.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and halogen substitutedC₁₋₄alkyl.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of hydrogen and C₁₋₄alkyl.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of hydrogen and methyl.

In an embodiment of the present invention, R⁶ is selected from the groupconsisting of C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, —C₁₋₄alkyl-CN,—C₁₋₄alkyl-OH, —C₁₋₄alkyl-Y—R⁹ and —CH₂-phenyl; wherein the phenyl isoptionally substituted with one to two substituent independentlyselected from halogen, C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,—O—C₁₋₄alkyl, —O-(halogen substituted C₁₋₄alkyl), nitro or cyano.

In another embodiment of the present invention, R⁶ is selected from thegroup consisting of C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,—C₁₋₄alkyl-CN, —C₁₋₄alkyl-OH, —C₁₋₄alkyl-Y—R⁹ and —CH₂-phenyl; whereinthe phenyl is optionally substituted with a halogen.

In another embodiment of the present invention, R⁶ is selected from thegroup consisting of C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,—C₁₋₄alkyl-CN, —C₁₋₄alkyl-OH and —C₁₋₄alkyl-Y—R⁹.

In another embodiment of the present invention, R⁶ is selected from thegroup consisting of C₁₋₄alkyl, halogen substituted C₁₋₄alkyl and—C₁₋₄alkyl-CN.

In another embodiment of the present invention, R⁶ is selected from thegroup consisting of methyl, chloro-methyl-, trifluoromethyl,cyano-methyl-, hydroxy-methyl, 3-fluoro-benzyl-, methoxy-methyl-,ethoxy-methyl-, methyl-thio-methyl-, ethyl-thio-methyl-,n-propyl-thio-methyl-, isopropyl-thio-methyl-,trifluoroethyl-thio-methyl-, benzyl-thio-methyl-,4-fluorophenyl-thio-methyl-, 4-methoxybenzyl-thio-methyl-,4-chlorobenzyl-thio-methyl-, 4-fluorobenzyl-thio-methyl-,methyl-sulfonyl-methyl-, ethyl-sulfonyl-methyl-,n-propyl-sulfonyl-methyl-, isopropyl-sulfonyl-methyl-,trifluoroethyl-sulfonyl-methyl-, 4-fluorophenyl-sulfonyl-methyl-,4-methylphenyl-sulfonyl-methyl-, 4-methylphenyl-sulfonyloxy-methyl-,benzyl-sulfonyl-methyl-, 4-fluorobenzyl-sulfonyl-methyl-,4-methoxybenzyl-sulfonyl-methyl- and4-methylcarbonylaminophenyl-sulfonyl-methyl-.

In an embodiment of the present invention, Y is selected from —O—, —S—,—SO—, —SO₂— and —O—SO₂—.

In another embodiment of the present invention, Y is selected from —O—,—S— and —SO₂—.

In another embodiment of the present invention, R⁹ is selected fromC₁₋₄alkyl, halogen substituted C₁₋₄alkyl, phenyl and —CH₂-phenyl;wherein the phenyl, whether alone or as part of a substituent group, isoptionally substituted with one or more substituents independentlyselected from halogen, C₁₋₄alkyl, —O—C₁₋₄alkyl or—NR^(M)—C(O)—C₁₋₄alkyl; wherein R^(M) is selected from hydrogen orC₁₋₂alkyl.

In another embodiment of the present invention, R⁹ is selected fromC₁₋₄alkyl, halogen substituted C₁₋₄alkyl and —CH₂-phenyl; wherein thephenyl is optionally substituted with one or more substituentsindependently selected from halogen, C₁₋₄alkyl or —O—C₁₋₄alkyl.

In an embodiment of the present invention, R¹⁰ is selected from thegroup consisting of hydrogen, halogen, C₁₋₄alkyl and

In another embodiment of the present invention, R¹⁰ is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and halogen substitutedC₁₋₄alkyl.

In another embodiment of the present invention, R¹⁰ is selected from thegroup consisting of hydrogen, fluoro, methyl and

In another embodiment of the present invention, R¹⁰ is hydrogen.

In an embodiment of the present invention, R¹¹ is selected from thegroup consisting of hydrogen, halogen and C₁₋₄alkyl.

In another embodiment of the present invention, R¹¹ is selected from thegroup consisting of hydrogen and halogen.

In another embodiment of the present invention, R¹¹ is selected from thegroup consisting of hydrogen and fluoro.

In another embodiment of the present invention, R¹¹ is hydrogen.

In an embodiment of the present invention, R¹⁰ and R¹¹ are takentogether with the carbon atom to which they are bound to form —C(O)— or—C(═N(OH))—.

In another embodiment of the present invention, R¹⁰ and R¹¹ are takentogether with the carbon atom to which they are bound to form —C(O)—.

In an embodiment of the present invention, R¹² is selected from thegroup consisting of C₁₋₄alkyl, halogen substituted C₁₋₄alkyl,—C₁₋₄alkyl-CN, —C₁₋₄alkyl-OH, —C₁₋₄alkyl-Y—R⁹ and —CH₂-phenyl; whereinthe phenyl is optionally substituted with one to two substituentindependently selected from halogen, C₁₋₄alkyl, halogen substitutedC₁₋₄alkyl, —O—C₁₋₄alkyl, —O-(halogen substituted C₁₋₄alkyl), nitro orcyano.

In another embodiment of the present invention, R¹² is selected from thegroup consisting of C₁₋₄alkyl, halogen substituted C₁₋₄alkyl and—C₁₋₄alkyl-CN.

In another embodiment of the present invention, R¹² is selected from thegroup consisting of C₁₋₄alkyl and halogen substituted C₁₋₄alkyl.

In another embodiment of the present invention, R¹² is selected from thegroup consisting of methyl, n-propyl, trifluoromethyl and2,2,2-trifluoroethyl.

In another embodiment of the present invention, R¹² is trifluoromethyl.

In an embodiment of the present invention R² and R³ are each other thanhydrogen.

In an embodiment of the present invention R¹ is other than —CH₂-phenyl.

In an embodiment of the present invention, when R⁴ is hydrogen and R⁵ ishydrogen or C₁₋₄alkyl; then R⁶ is other than C₁₋₄alkyl. In anotherembodiment of the present invention, R⁵ and R⁶ are not each C₁₋₄alkyl.In another embodiment of the present invention, R¹⁰ and R¹¹ are not eachC₁₋₄alkyl.

In an embodiment of the present invention, R⁶ is other than —CH₂-phenyl.In another embodiment of the present invention, R⁶ is other than—CH₂-benzimidazolyl.

In an embodiment of the present invention, R¹² is other than—CH₂-phenyl. In another embodiment of the present invention, R¹² isother than —CH₂-benzimidazolyl. In yet another embodiment of the presentinvention, R¹² is other than C₁₋₄alkyl.

In an embodiment of the present invention, wherein R¹⁰ and R¹¹ are takentogether with the carbon atom to which they are bound to form —C(O)—,then R¹² is other than C₁₋₄alkyl.

In an embodiment of the present invention are compounds of formula (I)selected from the group consisting of the compounds listed in Tables 1-3below. In another embodiment of the present invention are compounds offormula (II) selected from the group consisting of the compounds listedin Tables 4-6 below.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. R¹, R², R³, a, R⁴, R⁵, R⁶, X, Y, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,etc.) are independently selected to be any individual substituent or anysubset of substituents selected from the complete list as definedherein.

Representative compounds of the present invention are as listed inTables 1-6, below. Tables 1-3 list representative compounds of formula(I). Tables 4-6 list representative compounds of formula (II). Unlessotherwise noted, wherein a stereogenic center is present in the compound(as indicated by the “*” symbol), the compound was prepared as a mixtureof stereo-configurations.

TABLE 1 Representative Compounds of Formula (I)

ID No. R¹ R² R³ R⁵ R⁶ 1 H chloro chloro methyl 4-fluoro-phenyl-sulfonyl-methyl 2 H chloro chloro methyl 4-methyl-phenyl-sulfonyl-methyl 3 H chloro chloro methyl 3-fluoro-benzyl 4 H chlorochloro methyl hydroxy-methyl 5 H chloro chloro methyl methyl-sulfonyl-methyl 6 H chloro chloro methyl 4-methyl-phenyl- sulfonyloxy- methyl 7 Hchloro chloro methyl cyano-methyl 8 methyl chloro chloro methylcyano-methyl 9 methyl chloro chloro methyl trifluoro-methyl 10 methylchloro chloro methyl ethoxy-methyl 11 ethyl chloro chloro methylchloro-methyl 12 methyl chloro chloro methyl methyl-thio- methyl 13ethyl chloro chloro methyl trifluoro-methyl 14 n-propyl chloro chloromethyl trifluoro-methyl 15 n-butyl chloro chloro methyl trifluoro-methyl16 ethyl chloro chloro methyl cyano-methyl 17 ethyl chloro chloro methylmethoxy-methyl 18 methyl chloro chloro methyl chloro-methyl 20 H chlorochloro methyl trifluoro-methyl 21 methyl chloro chloro methyln-propyl-thio- methyl 22 methyl chloro chloro methyl 4-fluoro-phenyl-thio-methyl 23 methyl chloro chloro methyl benzyl-thio- methyl 24 methylchloro chloro methyl isopropyl-thio- methyl 25 methyl chloro chloromethyl ethyl-thio-methyl 29 methoxy- chloro chloro methyltrifluoro-methyl methyl 30 methoxy- chloro chloro methyl cyano-methylmethyl 31 ethyl chloro chloro methyl ethyl-thio-methyl 36 ethyl chlorochloro methyl 4-methoxy- benzyl-thio- methyl 38 ethyl chloro chloromethyl 4-chloro-benzyl- thio-methyl 39 ethyl chloro chloro methyl4-fluoro-benzyl- thio-methyl 40 methoxy- chloro chloro methyl methylmethyl 42 methyl chloro chloro methyl n-propyl-sulfonyl- methyl 44 ethylchloro chloro methyl trifluoro-ethyl- thio-methyl 45 methyl chlorochloro methyl benzyl-sulfonyl- methyl 46 ethyl chloro chloro methyl4-fluoro-benzyl- sulfonyl-methyl 47 ethyl chloro chloro methyl4-methoxy- benzyl-sulfonyl- methyl 48 ethyl chloro chloro methylethyl-sulfonyl- methyl 49 ethyl chloro chloro methyl trifluoro-ethyl-sulfonyl-methyl 51 methyl-thio- chloro chloro methyl methyl methyl 53cyano- chloro chloro methyl methyl methyl 54 methyl chloro chloro methylisopropyl- sulfonyl-methyl 55 methyl chloro chloro methylethyl-sulfonyl- methyl 56 methyl chloro chloro methyl 4-(methyl-carbonyl-amino)- phenyl-thio- methyl 64 methoxy- chloro chloro methylmethyl ethyl 66 cyano- chloro chloro methyl trifluoro-methyl methyl 59 Hchloro chloro H trifluoro-methyl 82^(a) H chloro chloro Htrifluoro-methyl 83^(a) H chloro chloro H trifluoro-methyl 111 H methylmethyl H trifluoro-methyl 112 H chloro fluoro H trifluoro-methyl 113 Hfluoro fluoro H trifluoro-methyl 128 H methyl chloro H trifluoro-methyl135 H trifluoro- cyano H trifluoro-methyl methyl 155 H nitro nitro Htrifluoro-methyl 156 H H chloro H trifluoro-methyl 157 H methoxy methoxyH trifluoro-methyl ^(a)Racemic compound #59 was reacted to yield amixture of diastereomers - the compounds #78 and compounds #107, whichwere then separated. The isolated compounds #78 and #107 were thenreacted to yield compounds #82 and #83, which were determined to have(−) and (+) optical rotation as noted.

TABLE 2 Representative Compounds of Formula (I)

ID No. R¹ R⁴ R⁵ R⁶ 28 methyl methyl methyl cyano-methyl 34 methyl methylmethyl trifluoro-methyl 35 H methyl methyl trifluoro-methyl 61 methylmethyl H trifluoro-methyl 62 ethyl ethyl H trifluoro-methyl 67 Ht-butyl-dimethyl-silyl- H trifluoro-methyl 78^(b) H

H trifluoro-methyl 107^(b) H

H trifluoro-methyl ^(b)Racemic compound #59 was reacted to yield amixture of diastereomers - the compounds #78 and #102, which were thenseparated.

TABLE 3 Representative Compounds of Formula (I)

ID No. R¹ R² R³ R⁵ R⁶ 27 H chloro chloro methyl trifluoromethyl 33methyl chloro chloro methyl trifluoromethyl 37 ethyl chloro chloromethyl trifluoromethyl

TABLE 4 Representative Compounds of Formula (II)

ID No. R¹ R² R³ W R⁶ 26 methoxy-methyl chloro chloro O methyl 114 Hchloro chloro O trifluoromethyl 141 H chloro chloro N(OH)trifluoromethyl 159 H fluoro chloro O trifluoromethyl 160 H methylchloro O trifluoromethyl

TABLE 5 Representative Compounds of Formula (II)

ID No. R¹ R² R³ 57 methoxy-methyl chloro chloro 58 methylthio-methylchloro chloro 41 H chloro chloro 68 H trifluoro-methyl chloro 69 Htrifluoro-methyl cyano 71 methyl chloro chloro 724-chloro-phenoxy-methyl chloro chloro 73 methyl-sulfonyl-methyl chlorochloro 74 phenyl-carbonyl-methyl chloro chloro 754-fluoro-phenyl-carbonyl- chloro chloro methyl 764-nitro-phenyl-carbonyl- chloro chloro methyl 77 2,4-dimethoxy-phenyl-chloro chloro carbonyl-methyl 79 4-bromo-phenyl-carbonyl- chloro chloromethyl 80 ethyl-carbonyl-methyl chloro chloro 81 ethoxy-carbonyl-methylchloro chloro 84 2-benzofuryl-carbonyl- chloro chloro methyl 854-chloro-phenyl-carbonyl- chloro chloro methyl 86 3-methoxy-phenyl-chloro chloro carbonyl-methyl 87 3-pyridyl-carbonyl-methyl chloro chloro88 2-(5-(2-pyridyl)-thienyl )- chloro chloro carbonyl-methyl 894-fluoro-benzyl chloro chloro 90 2-methoxy-phenyl- chloro chlorocarbonyl-methyl 91 2-thienyl-carbonyl-methyl chloro chloro 922-pyridyl-carbonyl-methyl chloro chloro 93 3-trifluoro-methyl-benzylchloro chloro 94 2,3,4,5,6-pentafluoro- chloro chloro benzyl 953-methyl-benzyl chloro chloro 96 3-nitro-phenyl-carbonyl- chloro chloromethyl 97 benzyl chloro chloro 98 2-hydroxy-ethyl chloro chloro 993-pyridyl-methyl chloro chloro 100 4-trifluoro-methyl-benzyl chlorochloro 101 4-trifluoro-methoxy-benzyl chloro chloro 102 2-pyridyl-methylchloro chloro 104 5-(2,3-dihydro- chloro chloro benzo[1,4]dioxinyl)-carbonyl-methyl- 105 4-nitro-benzyl chloro chloro 108 4-pyridyl-methylchloro chloro 109 3-cyano-methyl-benzyl chloro chloro 1102-cyano-methyl-benzyl chloro chloro 115 4-fluoro-phenoxy-ethyl chlorochloro 116 4-cyano-benzyl chloro chloro 117 2-fluoro-benzyl chlorochloro 119 3-fluoro-benzyl chloro chloro 120 3-chloro-benzyl chlorochloro 121 4-chloro-benzyl chloro chloro 123 3-fluoro-phenoxy-ethylchloro chloro 124 4-chloro-phenoxy-ethyl chloro chloro 1252-chloro-benzyl chloro chloro 126 3-phenyl-5-methyl- chloro chloroisoxazol-4-yl-carbonyl- methyl- 129 3-methoxy-benzyl chloro chloro 1302-methoxy-5-nitro-benzyl chloro chloro 131 4-pyrazolyl-benzyl chlorochloro 132 4-[1,2,3}-thiadiazol-4-yl- chloro chloro benzyl- 1333-(5-methyl)-isoxazolyl- chloro chloro methyl 1343-trifluoro-methoxy-benzyl chloro chloro 136 4-cyano-phenoxy-ethylchloro chloro 137 2-nitro-benzyl chloro chloro 138 4-pyrrolyl-benzylchloro chloro 139 3-nitro-benzyl chloro chloro 1404-trifluoromethyl-thio- chloro chloro benzyl 1424-methyl-sulfonyl-benzyl chloro chloro 144 trans-butan-2-one oximechloro chloro 145 trans-butan-2-one oxime chloro chloro 1464-benzyloxy-benzyl chloro chloro 147 4-methoxy-benzyl chloro chloro 1482-hydroxy-n-butyl chloro chloro 149 4-bromo-benzyl chloro chloro 1504-ethoxy-carbonyl-benzyl chloro chloro 151 2-bromo-benzyl chloro chloro153 4-benzaldehyde chloro chloro

TABLE 6 Representative Compounds of Formula (II)

ID No. R¹ R² R³ R¹⁰ R¹¹ R¹² 50 cyano-methyl chloro chloro methyl Hmethyl 60 methoxy-ethyl chloro chloro methyl H methyl 63 methoxy-methylchloro chloro methyl H methyl 65 methoxy-methyl chloro chloro methyl Hn-propyl 70 H chloro chloro H H 2,2,2- trifluoro-ethyl 106 H chlorochloro

H trifluoro-methyl 152 H chloro chloro fluoro H trifluoro-methyl 154 Hchloro chloro fluoro fluoro trifluoro-methyl

As used herein, unless otherwise noted, “halogen” shall mean chlorine,bromine, fluorine and iodine.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, shall include straight and branched chains. Forexample, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like. Similarly,“C₁₋₄alkyl” shall denote an alkyl chain as defined above comprising oneto four carbon atoms.

As used herein, unless otherwise noted, the term “halogen substitutedC₁₋₄alkyl” shall mean any of the above defined alkyl chains substitutedwith one or more, preferably one to three halogens. Preferably thehalogen(s) are selected from chloro or fluoro. Suitable examplesinclude, but are not limited to chloromethyl, dichloromethyl,fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

As used herein, unless otherwise noted, the terms “alkoxy” and“−O-alkyl” shall denote an oxygen ether radical of the above describedstraight or branched chain alkyl groups. For example, methoxy, ethoxy,n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. Similarly,“C₁₋₄alkoxy” or “—O—C₁₋₄alkyl” shall denote an oxygen ether radical asdefined above comprising one to four carbon atoms.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “aralkyl” shall mean any loweralkyl group substituted with an aryl group such as phenyl, naphthyl andthe like.

For example, benzyl, phenylethyl-, phenyl-n-propyl-, naphthylmethyl-,and the like. One skilled in the art will recognize that the terms“benzyl” and “—CH₂-phenyl” are used interchangeably throughout thespecification.

As used herein, unless otherwise noted, the term “cycloalkyl” shall meanany stable 3-8 membered monocyclic, saturated ring system, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered saturated, partially unsaturated orpartially aromatic bicyclic ring system containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heterocycloalkyl group maybe attached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,and the like.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., Phe, aryl, heteroalkyl,heteroaryl), that group may have one or more substituents, preferablyfrom one to five substituents, more preferably from one to threesubstituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a

“phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl” substituent refers to a groupof the formula

One skilled in the art will further recognize that some substituentgroups may begin or terminate with a “-”, as in for example,“ethyl-carbonyl-methyl-”. The presence of the “-” is intended, for thesake of clarity, to indicate the point of attachment between thesubstituent group and the rest of the molecule.

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

DCM=Dichloromethane

DMAC=N,N-Dimethylacetamide

DME=1,2-Dimethoxyethane

DMF=N,N-Dimethylformamide

DMSO=Dimethylsulfoxide

EtOAc=Ethyl acetate

mCPBA=m-Chloro-peroxybenzoic acid

MeOH=Methanol

NMP=N-methyl-2-pyrrolidinone

Oxone®=Potassium monopersulfate triple salt

TEMPO=2,2,6,6,-Tetramethyl-1-piperidinyloxy, free radical

THF=Tetrahydrofuran

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following: acids includingacetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid,alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitric acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Compounds of formula (I) wherein R⁴ is hydrogen may be preparedaccording to the process outlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (V), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (VI), a known compound orcompound prepared by known methods, in the presence of an acid such asHCl, H₂SO₄, acetic acid, and the like, in water, to yield thecorresponding compound of formula (Ia).

Alternatively, a suitably substituted compound of formula (V), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (VII), a known compound orcompound prepared by known methods, in the presence of sodium bisulfite,in water, to yield the corresponding compound of formula (Ia).

Alternatively, the compound of formula (V), a known compound or compoundprepared by known methods, is reacted with a suitably substitutedcompound of formula (VII), a known compound or compound prepared byknown methods, in the presence of Oxone® or silica supported thionylchloride, according to known methods, to yield the correspondingcompound of formula (Ia).

Alternatively still, the compound of formula (V) is reacted with asuitably substituted carboxylic acid derivative, such as a suitablysubstituted acid chloride or anhydride, a known compound or compoundprepared by known methods, according to known methods, followed bytreatment with an organic acid such as toluenesulfonic acid or with aLewis acid such as Al(CH₃)₃, (CH₃CH₂)₂AlCl, and the like, according toknown methods, to yield the corresponding compound of formula (Ia).

(See also for example, Mayer, J. P., Lewis, G. S., McGee, C.,Bankaitis-Davis, D., Tetrahedron Letters, 1998, 39(37) pp 6655-6658; BenAlloum, A., Bougrin, k., Soufiaoui, M., Tetrahedron letters, 2003,44(31) pp 5935-5937; Beaulieu, P. L., Hache, B., Von Moos, E.,Synthesis, 2003 (11), pp 1683-1692; and/or Matsushita, H., Lee, S-H.,Joung, M., Clapham, B., Janda, K. D., Tetrahedron Letters, 2004 45(2),pp 313-316)

The compound of formula (Ia) is optionally reacted with a suitablysubstituted compound of formula (VIII), a known compound or compoundprepared by known methods, or a suitably substituted compound of formula(IX), wherein L is a leaving group, a known compound or compoundprepared by known methods, in the presence of a base such as NaOH, KOH,NaH, K₂CO₃, and the like, in a polar, aprotic organic solvent such asacetonitrile, THF, DMF, and the like, to yield the correspondingcompound of formula (Ib).

The compound of formula (Ib) is optionally reacted with a dehydratingreagent such as Burgess' salt, and the like, in the presence of anorganic solvent such as THF, DMF, DCM, acetonitrile, toluene, and thelike, to yield the corresponding compound of formula (X).

The compound of formula (X), wherein a is 0, may be further, optionallyreacted with 1,3,5-trichloroisocyanoic acid, in a mixture of organicsolvent which is miscible with water and water such as acetone:water,THF:water, acetonitrile:water, DMF:water, dioxane:water, and the like,to yield the corresponding compound of formula (XI).

The compound of formula (XI) is reacted with a suitably substitutedcompound of formula (XII), a known compound or compound prepared byknown methods, in the presence of a base such as sodium methoxide,sodium t-butoxide, sodium hydride, and the like, in an organic solventsuch as DMF, THF, dioxane, methanol, and the like, to yield thecorresponding compound of formula (Ic).

One skilled in the art will recognize that compounds of formula (II) maybe similarly prepared according to the process outlined in Scheme 1above, by selecting and substituting, a suitably substituted compound offormula (XIII)

a known compound or compound prepared by known methods, for the compoundof formula (VI), to yield the corresponding compound of formula (IIa)

One skilled in the art will further recognize that the compound offormula (IIa) may then be further, optionally substituted with asuitably selected R¹ group, as outlined in Scheme 1 above.

One skilled in the art will recognize further that compounds of formula(I) wherein R⁴ is other than hydrogen may be prepared by reacting thecorresponding compound of formula (I) wherein R⁴ is hydrogen with asuitably substituted alkylating or acylating reagent, according to knownmethods.

Compounds of formula (I) may alternatively, be prepared according to theprocess outlined in Scheme 2.

Accordingly, a suitably substituted compound of formula (V), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XIV), a known compound orcompound prepared by known methods, in the presence of an acid such asHCl, H₂SO₄, acetic acid, and the like, in water, to yield thecorresponding compound of formula (XV).

The compound of formula (XV) is reacted with a suitably selectedoxidizing agent such as Na₂Cr₂O₇, and the like, in the presence of anacid such as sulfuric acid, and the like, in an aqueous solvent, toyield the corresponding compound of formula (XVI).

Alternatively, the compound of formula (XV) wherein R⁵ is hydrogen isreacted with a suitably selected oxidizing agent such as MnO₂ in asolvent such as dichloromethane, dichloroethane, benzene, toluene andthe like at a temperature range from room temperature to 110°,preferably at room temperature; Dess-Martin Periodinane in a solventsuch as dichloromethane, dichloroethane and the like at a temperaturerange from 0° C. to room temperature, preferably at room temperature; ora mixture of (a) TEMPO, (b) bleach and (c) KBr or NaBr, in an organicsolvent such as THF, DME, dioxane, and the like, at a reducedtemperature in the range of about −40° C. to about room temperature,preferably at a reduced temperature in the range of about −10 to about0° C.; to yield the corresponding compound of formula (XVI).

The compound of formula (XVI) is reacted with a suitably substitutedcompound of formula (XVII), wherein M is MgBr or Li, a known compound orcompound prepared by known methods, according to known methods, to yieldthe corresponding compound of formula (I) wherein R¹ is hydrogen.

Alternatively, the compound of formula (XVI) is reacted with a suitablysubstituted compound of formula (XVIII), wherein L is a suitable leavinggroup such as Br, I, and the like, a known compound or compound preparedby known methods, in the presence of an base such as NaH, K₂CO₃, Na₂CO₃,and the like, in an organic solvent such as DMF, DMAC, DMSO, NMP, andthe like, to yield the corresponding compound of formula (XIX).

The compound of formula (XIX) is reacted with a suitably substitutedcompound of formula (XVII), wherein M is MgBr or Li, a known compound orcompound prepared by known methods, according to known methods, to yieldthe corresponding compound of formula (I) wherein R¹ is other thanhydrogen.

One skilled in the art will recognize that compound of formula (II) maybe similarly prepared according to the process outlined in Scheme 2above, by selecting and substituting, suitably substituted startingmaterials and reagents.

One skilled in the art will further recognize that compounds of formula(II) wherein R¹⁰ and R¹¹ are taken together with the carbon atom towhich they are bound to form a group selected from —C═N(OH) or—C═N(O—C₁₋₄alkyl) may be prepared from the corresponding compound offormula (II) wherein R¹⁰ and R¹¹ are taken together with the carbon atomto which they are bound to form —C(O), according to known methods.

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) and/or (II) with apharmaceutically acceptable carrier. Pharmaceutical compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 50-100 mg and maybe given at a dosage of from about 0.5-5.0 mg/kg/day, preferably fromabout 1.0-3.0 mg/kg/day. The dosages, however, may be varied dependingupon the requirement of the patients, the severity of the conditionbeing treated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders or conditions modulated by the androgenreceptor described in the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.01 mg and 500 mg,preferably about 50 to 100 mg, of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Carriersinclude necessary and inert pharmaceutical excipients, including, butnot limited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixers, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders or conditions modulated by the androgenreceptor is required.

The daily dosage of the products may be varied over a wide range from0.01 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. An effectiveamount of the drug is ordinarily supplied at a dosage level of fromabout 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably,the range is from about 0.5 to about 5.0 mg/kg of body weight per day,most preferably, from about 1.0 to about 3.0 mg/kg of body weight perday. The compounds may be administered on a regimen of 1 to 4 times perday.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

Example 1 3-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-hydroxy-butyronitrile

CH₃CN was added to a solution of n-butyl lithium in THF (8 ml) at −78°C. and the mixture was stirred at −78° C. for 45 minutes. To thissolution was added 1-(5,6-dichloro-1H-benzimidazol-2-yl)-ethanone in THF(6 ml) and the resulting mixture was stirred at −78° C. for an addition½ hour. After stirring at 0° C. for 6 hrs, water was added, theresulting solution was extracted with EtOAc, the organic layer waswashed with brine and then dried over anhydrous Na₂SO₄. Solvent wasdistilled off under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes 10% to 50%) yielded the title product as an off-whitesolid.

MS m/z (M+H) 270

Example 22-(5,6-Dichloro-1-ethyl-1H-benzoimidazol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-propan-2-ol

To 1-chloro-2-(5,6-dichloro-1-ethyl-1H-benzoimidazol-2-yl)-propan-2-ol(249 mg) in methanol (5 mL) at room temperature was added a solution of2,2,2-trifluoroethanethiol (109 mg) and sodium methoxide (0.222 mls of25 wt % in MeOH). The resulting mixture was then stirred at roomtemperature overnight. The reaction mixture was concentrated. The crudeproduct was purified by flash chromatography (10%-40% EtOAc/hexanes) toyield the title compound as a brown solid.

¹H NMR (400 MHz, d₆-DMSO): δ 7.96 (s, 1H), 7.88 (s, 1H), 6.12 (s, 1H),4.53-4.61 (m, 2H), 3.48-3.54 (m, 2H), 3.31 (ABq, 2H, J_(AB)=13.3 Hz,Δν_(B)=71 Hz), 1.69 (s, 3H), 1.35 (t, 3H, J=7.0 Hz).

Example 32-(5,6-Dichloro-1-methyl-1H-benzoimidazol-2-yl)-1-phenylmethanesulfonyl-propan-2-ol

To a solution of2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-1-phenylmethanesulfanyl-propan-2-ol(76.5 mg) in CH₂Cl₂ (2 mL) at room temperature was added mCPBA (69 mg).The resulting mixture was stirred at room temperature overnight. Thereaction was then quenched with saturated NaHCO₃ (aq) and extracted withEtOAC. The crude product was purified by flash chromatography (10%-70%EtOAc/hexanes) to yield the title compound as a white foam.

¹H NMR (300 MHz, CDCl₃): δ 7.82 (s, 1H), 7.59-7.62 (m, 2H), 7.50 (s,1H), 7.42-7.44 (m, 3H), 5.09 (s, 1H), 4.56 (ABq, 2H, J_(AB)=13.7 Hz,Δν_(AB)=137 Hz), 4.02 (s, 3H), 3.86 (ABq, 2H, J_(AB)=15.1 Hz,Δν_(AB)=354 Hz), 1.68 (s, 3H).

Example 42-(5,6-Dichloro-1-ethyl-1H-benzoimidazol-2-yl)-1-(4-methoxy-phenylmethanesulfonyl)-propan-2-ol

To a solution of2-(5,6,-dichloro-1-ethyl-1H-benzoimidazol-2-yl)-1-(4-methoxy-phenylmethanesulfanyl)-propan-2-ol(97.6 mg) in CH₂Cl₂ (2 mL) at room temperature was added mCPBA (93 mg).The resulting mixture was stirred at room temperature overnight. Thereaction was quenched with saturated NaHCO₃ (aq) and extracted withEtOAc. The crude product was purified by flash chromatography (20%-60%EtOAc/hexanes) to yield the title compound as an off-white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.81 (s, 1H), 7.51 (s, 1H), 7.24 (ABq, 2H,J_(AB)=8.6 Hz, Δν_(AB)=173 Hz), 5.19 (s, 1H), 4.44 (ABq, 2H, J_(AB)=13.9Hz, Δν_(AB)=149 Hz), 4.41-4.69 (m, 2H), 3.85 (ABq, 2H, J_(AB)=15 Hz,Δν_(AB)=367 Hz), 3.83 (s, 3H), 1.68 (s, 3H), 1.48 (t, 3H, J=7.1 Hz).

Example 52-(5,6-Dichloro-1-ethyl-1H-benzoimidazol-2-yl)-1-ethylsulfanyl-propan-2-ol

To 1-chloro-2-(5,6-dichloro-1-ethyl-1H-benzoimidazol-2-yl)-propan-2-ol(161 mg) in methanol (5 mL) at room temperature was added a solution ofethanethiol (37 mg) and sodium methoxide (0.144 mls of 25 wt % in MeOH).The resulting mixture was stirred at room temperature overnight. Thereaction mixture was quenched with NH₄Cl (aq), extracted with EtOAc, anddried over Na₂SO₄. The crude product was purified by flashchromatography (10%-40% EtOAc/hexanes) to yield the title compound as anoff-white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.80 (s, 1H), 7.45 (s, 1H), 4.43-4.64 (m,2H), 3.77 (s, 1H), 3.35 (ABq, 2H, J_(AB)=13.6 Hz, Δν_(AB)=246 Hz),2.48-2.60 (m, 2H), 1.71 (s, 3H), 1.47 (t, 3H, J=7.2 Hz), 1.24 (t, 3H,J=7.4 Hz)

Example 62-(5,6-Dichloro-1-ethyl-1H-benzoimidazol-2-yl)-1-(2,2,2-trifluoro-ethanesulfonyl)-propan-2-ol

To2-(5,6-dichloro-1-ethyl-1H-benzoimidazol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-propan-2-ol(101 mg) in CH₂Cl₂ (2 mL) at room temperature was added mCPBA (106 mg).The resulting mixture was stirred at room temperature for 16 h. Thereaction was quenched with sat. NaHCO₃ (aq), extracted with EtOAc, driedover Na₂SO₄, filtered off dessicant, and concentrated. The residue waschromatographed with 10%-60% EtOAc/hexanes as the eluant to yield thetitle compound as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.74 (s, 1H), 7.50 (s, 1H), 4.87-5.01 (m,1H), 4.83 (s, 1H), 4.41-4.66 (m, 2H), 4.16 (ABq, 2H, J_(AB)=15.4 Hz,Δν_(AB)=334 Hz), 3.78-3.93 (m, 1H), 1.71 (s, 3H), 1.48 (t, 3H, J=7.2Hz).

Example 72-(5,6-Dichloro-1-ethyl-1H-benzoimidazol-2-yl)-1-ethanesulfonyl-propan-2-ol

To2-(5,6-dichloro-1-ethyl-1H-benzoimidazol-2-yl)-1-ethanesulfanyl-propan-2-ol(134.8 mg) in CH₂Cl₂ (2 mL) at room temperature was added mCPBA (164mg). The resulting mixture was stirred at room temperature for 16 h. Thereaction was quenched with saturated NaHCO₃ (aq), extracted with EtOAc,dried over Na₂SO₄, filtered off dessicant, and concentrated. The residuewas chromatographed with 10%-60% EtOAc/hexanes as the eluant to yieldthe title compound as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.74 (s, 1H), 7.49 (s, 1H), 5.25 (s, 1H),4.40-4.72 (m, 2H), 3.96 (ABq, 2H, J_(AB)=14.8 Hz, Δν_(AB)=289 Hz),3.00-3.26 (m, 2H), 1.74 (s, 3H), 1.47 (t, 3H, J=7.2 Hz), 1.41 (t, 3H,J=7.8 Hz).

Example 81-Chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol

To 5,6-dichloro-1-methyl-2-isopropenyl-1H-benzimidazole (2.5 g) inacetone (30 mL) and water (6 mL) at room temperature was addedtrichloroisocyanuric acid (845 mg). The resulting mixture was stirred atroom temperature for 18 h. The reaction mixture was quenched with water,extracted with EtOAc, and dried over Na₂SO₄. After removal of thedessicant by filtration, concentration yielded an orange crude oil. Thecrude product was purified by flash chromatography (10%-40%EtOAc/hexanes) to yield the title compound as a yellow solid.

¹H NMR (400 MHz, d₆-DMSO): δ 7.97 (s, 1H), 7.90 (s, 1H), 6.22 (s, 1H),4.04 (m, 2H), 4.01 (s, 3H), 1.68 (s, 3H)

Example 92-(5,6-Dichloro-1-methyl-1H-benzoimidazol-2-yl)-1-isobutylsulfanyl-propan-2-ol

To 1-chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol(408 mg) in methanol (10 mL) at room temperature was added a solution of2-methyl-1-propanethiol (150 mg) and sodium methoxide (0.381 mls of 25wt % in MeOH). The resulting mixture was stirred at room temperatureovernight. The reaction mixture was then concentrated. The crude productwas purified by flash chromatography (10%-40% EtOAc/hexanes) to yieldthe title compound as a light orange solid.

¹H NMR (300 MHz, CDCl₃): δ7.80 (s, 1H), 7.43 (s, 1H), 4.00 (s, 3H), 3.75(s, 1H), 3.33 (ABq, 2H, J_(AB)=13.6 Hz, Δν_(AB)=248 Hz), 2.36-2.51 (m,2H), 1.73-1.83 (m, 1H), 1.70 (s, 3H), 0.95 (d, 6H, J=6.8 Hz)

MS (M+1)=347.1; (M+Na)=369.1.

Example 102-(5,6-Dichloro-1-methyl-1H-benzoimidazol-2-yl)-1-(2-methyl-propane-1-sulfonyl)-propan-2-ol

To2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-1-isobutylsulfanyl-propan-2-ol(97 mg) in CH₂Cl₂ (2 mL) at room temperature was added mCPBA (113 mg)and subsequently stirred overnight. The reaction mixture was quenchedwith NaHCO₃ (aq), extracted with EtOAc, and dried over Na₂SO₄. The crudeproduct was purified by flash chromatography (10%-70% EtOAc/hexanes) toyield the title compound as an off-white solid.

¹H NMR (300 MHz, CDCl₃): δ7.73 (s, 1H), 7.48 (s, 1H), 5.17 (s, 1H), 4.02(s, 3H), 3.96 (ABq, 2H, J_(AB)=14.9 Hz, Δν_(AB)=260 Hz), 2.37 (nonet,1H, J=6.7 Hz), 1.73 (s, 3H), 1.12 (d, 3H, J=6.7 Hz), 1.07 (d, 3H, J=6.7Hz).

Example 112-(5,6-Dichloro-1-methyl-1H-benzoimidazol-2-yl)-1-ethylsulfanyl-propan-2-ol

To 1-chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol(141 mg) in MeOH (4 mL) at room temperature was added a solution ofethanethiol (34 mg) and sodium methoxide (0.132 mls of 25 wt % in MeOH).The resulting mixture was stirred at room temperature overnight. Thereaction mixture was then concentrated. The crude product was purifiedby flash chromatography (10%-40% EtOAc/hexanes) to yield the titlecompound as a yellow crystalline solid.

¹H NMR (300 MHz, CDCl₃): δ 7.80 (s, 1H), 7.43 (s, 1H), 4.00 (s, 3H),3.74 (s, 1H), 3.34 (ABq, 2H, J_(AB)=13.7 Hz, Δν_(AB)=246 Hz), 2.48-2.62(m, 2H), 1.71 (3, 3H), 1.25 (t, 3H, J=7.4 Hz)

MS (M+1)=319.0.

Example 12N-{4-[2-(5,6-Dichloro-1-methyl-1H-benzoimidazol-2-yl)-2-hydroxy-propylsulfanyl]-phenyl}-acetamide

To 1-chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol(60 mg) in MeOH (2 mL) at room temperature was added a solution of4-acetamidothiophenol (40 mg) and sodium methoxide (0.047 mls of 25 wt %in MeOH). The resulting mixture was stirred at room temperatureovernight. The reaction mixture was concentrated. The crude product waspurified by flash chromatography (25%-100% EtOAc/hexanes) to yield thetitle compound as a white foam solid.

¹H NMR (300 MHz, CDCl₃): δ 7.72 (s, 1H), 7.29 (s, 1H), 7.27 (s, 1H),7.20 (s, 4H), 3.85 (s, 3H), 3.83 (s, 1H), 3.62 (ABq, 2H, J_(AB)=14 Hz,Δν_(AB)=179 Hz), 2.16 (s, 3H), 1.76 (s, 3H)

MS (M+1)=424.0; (M+Na)=446.0

Example 13 5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 4,5-dichloro-1,2-phenylenediamine (25 g) was added3,3,3-trifluoropropionic acid (25 mls) and 4N HCl (90 mL). The resultingmixture was heated to 100° C. overnight. The reaction mixture wasquenched with water, basicified with concentrated NH₄OH, extracted withEtOAc, and dried over Na₂SO₄. The crude product was filtered through aplug of silica gel, eluting with 30% EtOAc/hexanes, and collecting thered band. The fractions were concentrated to yield a mixture of thedesired title compound and 4,5-dichloro-1,2-phenylenediamine. The crudematerial was dissolved in small amount of CH₂Cl₂ and triturated withhexanes to yield the title compound as a tan solid.

¹H NMR (300 MHz, d₆-DMSO): δ 12.92 (br s, 1H), 7.88 (s, 2H), 4.06 (ABq,2H, J_(AB)=11 Hz, Δν_(AB)=19 Hz).

Example 142-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-phenyl-ethanone

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (301 mg) inDMF (5 mL) was added sodium hydride (67 mg of 60% in oil dispersion).The resulting mixture was stirred at room temperature for 5 min. To thedark green solution was added 2-bromo-acetophenone (273 mg) and theresulting mixture was stirred at room temperature overnight. Thereaction mixture was quenched with water, extracted with EtOAc, anddried over Na₂SO₄. The crude product was purified by silica gelchromatography (10%-40% EtOAc/hexanes) to yield the title compound as anoff-white solid.

¹H NMR (300 MHz, CDCl₃): δ 8.04-8.07 (m, 2H), 7.92 (s, 1H), 7.73-7.78(m, 1H), 7.59-7.64 (m, 2H), 7.29 (s, 1H), 5.59 (s, 2H), 3.72 (ABq, 2H,J_(AB)=9.9 Hz, Δν_(AB)=17.2 Hz).

Example 152-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(4-fluoro-phenyl)-ethanone

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (318 mg) inDMF (5 mL) was added sodium hydride (71 mg of 60% in oil dispersion).The resulting mixture was stirred at room temperature for 5 min. To thedark green solution was added 2-bromo-4′ fluoroacetophenone (317 mg) andthe resulting mixture was stirred at room temperature overnight. Thereaction mixture was quenched with water, extracted with EtOAc, anddried over Na₂SO₄. The crude product was purified by silica gelchromatography (10%-40% EtOAc/hexanes) to yield the title compound as apeach colored solid.

¹H NMR (300 MHz, CDCl₃): δ 8.07-8.12 (m, 2H), 7.92 (s, 1H), 7.25-7.32(m, 3H), 5.56 (s, 2H), 3.72 (ABq, 2H, J_(AB)=9.9 Hz, Δν_(AB)=17.2 Hz).

Example 162-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(4-nitro-phenyl)-ethanone

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (304 mg) inDMF (5 mL) was added sodium hydride (68 mg of 60% in oil dispersion).The resulting mixture was stirred at room temperature for 5 min. To thedark green solution was added 2-bromo-4′ nitroacetophenone (348 mg) andthe resulting mixture was stirred at room temperature overnight. Thereaction mixture was quenched with water, extracted with EtOAc, anddried over Na₂SO₄. The crude product was purified by silica gelchromatography (10%-40% EtOAc/hexanes) to yield the title compound as anorange colored solid.

Example 172-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(2,4-dimethoxy-phenyl)-ethanone

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (317 mg) inDMF (5 mL) was added sodium hydride (71 mg of 60% in oil dispersion).The resulting mixture was stirred at room temperature for 5 min. To thedark green solution was added 2-bromo-2′,4′-dimethoxyacetophenone (382mg) and the resulting mixture was stirred at room temperature overnight.The reaction mixture was quenched with water, extracted with EtOAc, anddried over Na₂SO₄. The crude product was purified by silica gelchromatography (10%-40% EtOAc/hexanes) to yield the title compound as awhite solid.

¹H NMR (300 MHz, d₆-DMSO): δ 7.97 (s, 1H), 7.96 (s, 1H), 7.78 (d, 1H,J=7.0 Hz), 6.67-6.70 (m, 1H), 5.75 (s, 2H), 4.13 (ABq, 2H, J_(AB)=11 Hz,Δν_(AB)=19 Hz), 4.03 (s, 3H), 3.89 (s, 3H).

Example 185,6-Dichloro-1-methyl-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (1 g) in DMF(20 mL) was added sodium hydride (230 mg of 60% in oil dispersion). Theresulting mixture was stirred at room temperature for 5 min. To the darkgreen solution was added iodomethane (815 mg) and the resulting mixturewas stirred at room temperature overnight. The reaction mixture wasquenched with water, extracted with EtOAc, and dried over Na₂SO₄. Thecrude product was purified by silica gel chromatography (5%-25%EtOAc/hexanes) to yield the title compound as an orange solid.

¹H NMR (300 MHz, CDCl₃): δ 7.85 (s, 1H), 7.46 (s, 1H), 3.80 (ABq, 2H,J_(AB)=9.9 Hz, Δν_(AB)=14 Hz), 3.79 (s, 3H).

Example 19[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-acetic acidethyl ester

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (1 g) in DMF(5 mL) was added sodium hydride (85 mg of 60% in oil dispersion). Theresulting mixture was stirred at room temperature for 5 min. To the darkgreen solution was added ethyl bromoacetate (363 mg) and the resultingmixture was stirred at room temperature overnight. The reaction mixturewas quenched with water, extracted with EtOAc, and dried over Na₂SO₄.The crude product was purified by silica gel chromatography (5%-30%EtOAc/hexanes) to yield the title compound as a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 7.89 (s, 1H), 7.40 (s, 1H), 4.86 (s, 2H),4.26 (q, 2H, J=7.1 Hz), 3.79 (ABq, 2H, J_(AB)=9.9 Hz, Δν_(AB)=17.1 Hz),1.29 (t, 3H, J=7.1 Hz).

Example 201-Benzofuran-2-yl-2-[5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-ethanone

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (460.5 mg) inDMF (5 mL) was added sodium hydride (103 mg of 60% in oil dispersion).The resulting mixture was stirred at room temperature for 5 min. To thedark green solution was added 1-(1-benzofuran-2-yl)-2-bromoethan-1-one(633 mg) and the resulting mixture was stirred at room temperatureovernight. The reaction mixture was quenched with water, extracted withEtOAc, and dried over Na₂SO₄. The crude product was purified by silicagel chromatography (10%-40% EtOAc/hexanes) to yield the title compoundas a yellow solid.

¹H NMR (300 MHz, d₆-DMSO): δ 8.10 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H),7.95 (d, 1H, J=7.8 Hz), 7.81 (d, 1H, J=8.1 Hz), 7.62 (t, 1H, J=7.4 Hz),7.44 (t, 1H, J=7.4 Hz), 6.05 (s, 2H), 4.23 (ABq, 2H, J_(AB)=10.6 Hz,Δν_(AB)=18.6 Hz).

Example 215,6-Dichloro-1-(4-fluoro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (301 mg) inDMF (5 mL) was added potassium carbonate powder (298 mg) and4-fluorobenzyl bromide (841 mg). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was quenched withwater, extracted with EtOAc, and dried over Na₂SO₄. The crude productwas purified by silica gel chromatography (10%-40% EtOAc/hexanes) toyield the title compound as a peach colored solid.

MS (M−1)=375.0.

Example 225,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1-(3-trifluoromethyl-benzyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (355 mg) inDMF (5 mL) was added potassium carbonate powder (548 mg) and3-trifluoromethylbenzyl bromide (947 mg). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith water, extracted with EtOAc, and dried over Na₂SO₄. The crudeproduct was purified by silica gel chromatography (10%-40%EtOAc/hexanes) to yield the title compound as an orange solid.

¹H NMR (300 MHz, CDCl₃): δ 7.94 (s, 1H), 7.62 (d, 1H, J=8.0 Hz), 7.48(t, 1H, J=7.8 Hz), 7.36 (s, 1H), 7.30 (s, 1H), 7.05 (d, 1H, J=8.1 Hz),5.45 (s, 2H), 3.73 (ABq, 2H, J_(AB)=9.7 Hz, Δν_(AB)=17 Hz).

Example 235,6-Dichloro-1-pentafluorophenylmethyl-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (354 mg) inDMF (5 mL) was added potassium carbonate powder (545 mg) and2,3,4,5,6-pentafluoromethylbenzyl bromide (1.028 g). The resultingmixture was stirred at room temperature overnight. The reaction mixturewas quenched with water, extracted with EtOAc, and dried over Na₂SO₄.The crude product was purified by silica gel chromatography (10%-40%EtOAc/hexanes) to yield the title compound as a tan solid.

Example 245,6-Dichloro-1-(3-methyl-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (360 mg) inDMF (5 mL) was added potassium carbonate powder (555 mg) and3-methylbenzyl bromide (774 mg). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was quenched withwater, extracted with EtOAc, and dried over Na₂SO₄. The crude productwas purified by silica gel chromatography (10%-40% EtOAc/hexanes) toyield the title compound as an off-white solid.

Example 255,6-Dichloro-1-pyridin-3-ylmethyl-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (423 mg) inDMF (5 mL) was added potassium carbonate powder (868 mg) and3-(bromomethyl)pyridine hydrogen bromide (615 mg). The resulting mixturewas stirred at room temperature overnight. The reaction mixture wasquenched with water, extracted with EtOAc, and dried over Na₂SO₄. Thecrude product was purified by silica gel chromatography (15%-60%EtOAc/hexanes) to yield the title compound as a green solid.

Example 265,6-Dichloro-1-(4-nitro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (355 mg) inDMF (5 mL) was added sodium hydride (110 mg of 60% in oil) and4-nitrobenzyl bromide (596 mg). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was quenched withwater, extracted with EtOAc, and dried over Na₂SO₄. The crude productwas purified by silica gel chromatography (10%-40% EtOAc/hexanes) toyield the title compound as a light orange solid.

¹H NMR (300 MHz, CDCl₃): δ 8.20 (d, 2H, J=8.8 Hz), 7.92 (s, 1H), 7.26(s, 1H), 7.16 (d, 2H, J=8.8 Hz), 5.50 (s, 2H), 3.75 (ABq, 2H, J_(AB)=9.7Hz, Δν_(AB)=23 Hz).

Example 272-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-ethanol

To [5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzimidazol-1-yl]-aceticacid ethyl ester (915 mg) in toluene (20 mL) at −78° C. was addedDiBAI-H (3.43 mls of 1.5 M in toluene). The resulting mixture wasstirred for 1 hour. The reaction mixture was quenched with Rochelle'ssalt (aq), extracted with EtOAc, and dried over Na₂SO₄. The extractswere concentrated to a toluene solution and ethanol (10 mL) was added.To the resulting solution was added NaBH₄ (533 mg). The resultingmixture was stirred for 5 hour. The reaction mixture was quenched withwater, extracted with EtOAc, and dried over Na₂SO₄. The crude productwas purified by silica gel chromatography (15%-60% EtOAc/hexanes) toyield the title compound as a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 7.41 (s, 1H), 7.37 (s, 1H), 4.37 (t, 1H,J=5.1 Hz), 4.30 (t, 2H, J=4.6 Hz), 3.99-4.03 (m, 2H), 3.86 (ABq, 2H,J_(AB)=9.8 Hz, Δν_(AB)=17 Hz).

Example 285,6-Dichloro-1-[2-(4-fluoro-phenoxy)-ethyl]-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To a mixture of2-[5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzomidazol-1-yl]-ethanol(171 mg), 4-fluorophenol (92 mg), and triphenylphosphine (158 mg) intoluene (5 mL) at 0° C. was added diethylazodicarboxylate (0.11 mls).The resulting mixture was stirred at ambient temperature overnight. Thereaction mixture was quenched with 1N HCl (aq), extracted with EtOAc,and dried over Na₂SO₄. The crude product was purified by silica gelchromatography (4%-25% EtOAc/hexanes) to yield the title compound as awhite solid.

Example 295,6-Dichloro-1-[2-(3-fluoro-phenoxy)-ethyl]-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To a mixture of2-[5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzomidazol-1-yl]-ethanol(164 mg), 3-fluorophenol (88 mg), and triphenylphosphine (158 mg) intoluene (5 mL) at 0° C. was added diethylazodicarboxylate (0.11 mls).The resulting mixture was stirred at ambient temperature overnight. Thereaction mixture was quenched with 1N HCl (aq), extracted with EtOAc,and dried over Na₂SO₄. The crude product was purified by silica gelchromatography (4%-25% EtOAc/hexanes) to yield the title compound as anoff-white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.86 (s, 1H), 7.55 (s, 1H), 7.16-7.24 (m,1H), 6.64-6.71 (m, 1H), 6.47-6.58 (m, 2H), 4.59 (t, 2H, J=4.8 Hz), 4.25(t, 2H, J=5.0 Hz), 3.99 (ABq, 2H, J_(AB)=9.9 Hz, Δν_(AB)=17 Hz).

Example 305,6-Dichloro-1-[2-(4-chloro-phenoxy)-ethyl]-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To a mixture of2-[5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzomidazol-1-yl]-ethanol(153 mg), 4-chlorophenol (94 mg), and triphenylphosphine (141 mg) intoluene (5 mL) at 0° C. was added diethylazodicarboxylate (0.10 mls).The resulting mixture was stirred at ambient temperature overnight. Thereaction mixture was quenched with 1N HCl (aq), extracted with EtOAc,and dried over Na₂SO₄. The crude product was purified by silica gelchromatography (4%-25% EtOAc/hexanes) to yield the title compound as awhite foamy solid.

Example 315,6-Dichloro-1-(3-methoxy-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (368 mg) inDMF (5 mL) was added potassium carbonate powder (567 mg) and3-methoxybenzyl bromide (825 mg). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was quenched withwater, extracted with EtOAc, and dried over Na₂SO₄. The crude productwas purified by silica gel chromatography (10%-40% EtOAc/hexanes),followed by dissolution in CH₂Cl₂ and trituration with hexanes to yieldthe title compound as a peach solid.

¹H NMR (300 MHz, CDCl₃): δ 7.91 (s, 1H), 7.37 (s, 1H), 7.26 (t, 1H,J=6.7 Hz), 6.86 (dd, 1H, J=8.3, 2.3 Hz), 6.55 (d, 1H, J=7.6 Hz), 6.51(s, 1H), 5.34 (s, 2H), 3.75 (s, 3H), 3.71 (ABq, 2H, J_(AB)=9.8 Hz,Δν_(AB)=17 Hz).

Example 325,6-Dichloro-1-(2-methoxy-5-nitro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (387 mg) inDMF (5 mL) was added potassium carbonate powder (596 mg) and3-methoxy-5-nitro-benzyl bromide (1.06 g). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith water, extracted with EtOAc, and dried over Na₂SO₄. The crudeproduct was purified by silica gel chromatography (10%-40%EtOAc/hexanes) to yield the title compound as a peach-colored solid.

¹H NMR (300 MHz, CDCl₃): δ 8.25 (dd, 1H, J=9.1, 2.7 Hz), 7.91 (s, 1H),7.58 (d, 1H, J=2.5 Hz), 7.33 (s, 1H), 7.03 (d, 1H, J=9.1 Hz), 5.37 (s,2H), 4.01 (s, 3H), 3.82 (ABq, 2H, J_(AB)=9.7 Hz, Δν_(AB)=17 Hz).

Example 334-{2-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-ethoxy}-benzonitrile

To a mixture of2-[5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzomidazol-1-yl]-ethanol(142 mg), 4-cyanophenol (81 mg), and triphenylphosphine (143 mg) intoluene (5 mL) at 0° C. was added ditert-butylazodicarboxylate (125 mg).The resulting mixture was stirred at ambient temperature overnight. Tothe mixture was added 2 drops of trifluoroacetic acid and stirred for 4hours. The reaction mixture was quenched with 1N HCl (aq), extractedwith EtOAc, and dried over Na₂SO₄. The crude product was purified bysilica gel chromatography (5%-30% EtOAc/hexanes) to yield the titlecompound as a white foamy solid.

¹H NMR (300 MHz, CDCl₃): δ 7.88 (s, 1H), 7.57 (s, 1H), 7.58 (d, 2H,J=8.6 Hz), 6.86 (d, 2H, J=8.7 Hz), 4.63 (t, 2H, J=4.8 Hz), 4.33 (t, 2H,J=4.9 Hz), 3.97 (ABq, 2H, J_(AB)=9.8 Hz, Δν_(AB)=17 Hz).

Example 345,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1-(3-trifluoromethoxy-benzyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (495 mg) inDMF (5 mL) was added potassium carbonate powder (763 mg) and3-(trifluoromethoxy)benzyl bromide (1.41 g). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith water, extracted with EtOAc, and dried over Na₂SO₄. The crudeproduct was purified by silica gel chromatography (10%-40%EtOAc/hexanes) to yield the title compound as a brown solid.

¹H NMR (300 MHz, CDCl₃): δ 7.90 (s, 1H), 7.39 (t, 1H, J=8.0 Hz), 7.31(s, 1H), 7.20 (d, 1H, J=8.3 Hz), 6.89 (s, 1H), 6.87 (d, 1H, J=8.7 Hz),5.40 (s, 2H), 3.73 (ABq, 2H, J_(AB)=9.8 Hz, Δν_(AB)=17 Hz).

Example 355,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1-(4-trifluoromethylsulfanyl-benzyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (434 mg) inDMF (5 mL) was added potassium carbonate powder (669 mg) and4-(trifluoromethylthio) benzyl bromide (596 mg). The resulting mixturewas stirred at room temperature overnight. The reaction mixture wasquenched with water, extracted with EtOAc, and dried over Na₂SO₄. Thecrude product was purified by silica gel chromatography (10%-40%EtOAc/hexanes) to yield the title compound as a brown solid.

¹H NMR (300 MHz, CDCl₃): δ 7.91 (s, 1H), 7.64 (d, 2H, J=8.2 Hz), 7.31(s, 1H), 7.03 (d, 2H, J=8.3 Hz), 5.42 (s, 2H), 3.71 (ABq, 2H, J_(AB)=9.8Hz, Δν_(AB)=17 Hz).

Example 365,6-Dichloro-1-(2-nitro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (319 mg) inDMF (5 mL) was added potassium carbonate powder (491 mg) I) and2-nitrobenzyl bromide (768 mg). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was quenched withwater, extracted with EtOAc, and dried over Na₂SO₄. The crude productwas purified by silica gel chromatography (5%-35% EtOAc/hexanes),followed by dissolution in CH₂Cl₂ and trituration with hexanes to yieldthe title compound as orange solid.

¹H NMR (300 MHz, CDCl₃): δ 7.96 (s, 1H), 7.49-7.61 (m, 2H), 7.24 (s,1H), 6.42-6.45 (m, 1H), 5.83 (s, 2H), 3.74 (ABq, 2H, J_(AB)=9.7 Hz,Δν_(AB)=17 Hz).

Example 375,6-Dichloro-1-(3-nitro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (355 mg) inDMF (5 mL) was added sodium hydride (110 mg of 60% in oil) and3-nitrobenzyl bromide (596 mg). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was quenched withwater, extracted with EtOAc, and dried over Na₂SO₄. The crude productwas purified by silica gel chromatography (10%-40% EtOAc/hexanes) toyield the title compound as a red solid.

¹H NMR (300 MHz, CDCl₃): δ 8.22 (d, 1H, J=7.8 Hz), 7.96 (d, 1H, J=11.8Hz), 7.94 (s, 1H), 7.56 (t, 1H, J=7.9 Hz), 7.27 (s, 1H), 7.21 (s, 1H,J=7.7 Hz), 5.50 (s, 2H), 3.76 (ABq, 2H, J_(AB)=9.5 Hz, Δν_(AB)=17 Hz).

Example 385,6-Dichloro-1-(4-methanesulfonyl-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (483 mg) inDMF (5 mL) was added potassium carbonate powder (744 mg) and4-methylsulphonylbenzyl bromide (1.68 g). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith water, extracted with EtOAc, and dried over Na₂SO₄. The crudeproduct was purified by silica gel chromatography (10%-40%-75%EtOAc/hexanes) to yield the title compound as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 7.94 (s, 1H), 7.93 (d, 2H, J=7.9 Hz), 7.27(s, 1H), 7.17 (d, 2H, J=8.3 Hz), 5.48 (s, 2H), 3.74 (ABq, 2H, J_(AB)=9.7Hz, Δν_(AB)=17 Hz), 3.06 (s, 3H).

Example 39[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-acetonitrile

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (356 mg) inDMF (5 mL) was added sodium hydride (79 mg of 60% in oil) andiodoacetonitrile (331 mg). The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with water,extracted with EtOAc, and dried over Na₂SO₄. The crude product waspurified by silica gel chromatography (10%-40% EtOAc/hexanes), followedby washing solid with CH₂Cl₂ to yield the title compound as apeach-colored solid.

¹H NMR (300 MHz, d₆-DMSO): δ 8.15 (s, 1H), 8.07 (s, 1H), 5.73 (s, 2H),4.31 (ABq, 2H, J_(AB)=11 Hz, Δν_(AB)=19 Hz).

Example 405,6-Dichloro-1-(2-methyl-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (583 mg) inDMF (6 mL) was added potassium carbonate powder (900 mg) and2-methylbenzyl bromide (1.2 g). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was quenched withwater, extracted with EtOAc, and dried over Na₂SO₄. The crude productwas purified by silica gel chromatography (10%-40% EtOAc/hexanes),followed by washing solid with hexanes to yield the title compound as atan solid.

¹H NMR (300 MHz, CDCl₃): δ 7.93 (s, 1H), 7.29 (s, 1H), 7.22-7.26 (m,2H), 7.04-7.10 (m, 1H), 6.31 (d, 1H, J=7.9 Hz), 5.33 (s, 2H), 3.65 (ABq,2H, J_(AB)=9.8 Hz, Δν_(AB)=17 Hz).

Example 415,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1-(2-trifluoromethyl-benzyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (577 mg) inDMF (6 mL) was added potassium carbonate powder (890 mg) and2-(trifluoromethyl)benzyl bromide (1.54 g). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith water, extracted with EtOAc, and dried over Na₂SO₄. The crudeproduct was purified by silica gel chromatography (5%-40%EtOAc/hexanes), followed by recrystallization with hexanes to yield thetitle compound as an orange-brown solid.

¹H NMR (300 MHz, CDCl₃): δ 7.95 (s, 1H), 7.80 (d, 1H, J=7.2 Hz),7.38-7.48 (m, 2H), 7.29 (s, 1H), 6.44 (d, 1H, J=7.5 Hz), 5.58 (s, 2H),3.68 (ABq, 2H, J_(AB)=9.7 Hz, Δν_(AB)=17 Hz).

MS (M+1)=427.0

Example 421-(2,4-Bis-trifluoromethyl-benzyl)-5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (622 mg) inDMF (7 mL) was added potassium carbonate powder (958 mg) and2,4-bis(trifluoromethyl)-benzyl bromide (2.13 g). The resulting mixturewas stirred at room temperature overnight. The reaction mixture wasquenched with water, extracted with EtOAc, and dried over Na₂SO₄. Thecrude product was purified by silica gel chromatography (5%-40%EtOAc/hexanes), followed by recrystallization with hexanes to yield thetitle compound as an orange solid.

¹H NMR (300 MHz, CDCl₃): δ 8.05 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H,J=8.1 Hz), 7.25 (s, 1H), 6.59 (d, 1H, J=8.2 Hz), 5.63 (s, 2H), 3.71(ABq, 2H, J_(AB)=9.7 Hz, Δν_(AB)=17 Hz).

MS (M−1)=492.9

Example 431-(2-Benzenesulfonylmethyl-benzyl)-5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (629 mg) inDMF (7 mL) was added potassium carbonate powder (969 mg) and1-bromomethyl-2-[phenylsulfonyl)methyl]benzyl bromide (2.28 g). Theresulting mixture was stirred at room temperature overnight. Thereaction mixture was quenched with water, extracted with EtOAc, anddried over Na₂SO₄. The crude product was purified by silica gelchromatography (5%-40% EtOAc/hexanes), followed by recrystallizationwith hexanes to yield the title compound as a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 7.94 (s, 1H), 7.78 (d, 1H, J=7.1 Hz),7.69-7.77 (m, 1H), 7.59 (d, 2H, J=7.9 Hz), 7.36 (s, 1H), 7.14-7.23 (m,2H), 6.89 (dd, 1H, J=6.8, 1.5 Hz), 6.32 (dd, 1H, J=8.7, 6.8 Hz), 5.69(s, 2H), 4.44 (s, 2H), 3.76 (ABq, 2H, J_(AB)=9.8 Hz, Δν_(AB)=17 Hz).

Example 441-Biphenyl-2-ylmethyl-5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (521 mg) inDMF (5 mL) was added potassium carbonate powder (802 mg) and 2-phenylbenzyl bromide (1.43 g). The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with water,extracted with EtOAc, and dried over Na₂SO₄. The crude product waspurified by silica gel chromatography (5%-40% EtOAc/hexanes), followedby recrystallization with Et₂O/hexanes to yield the title compound as awhite solid.

¹H NMR (300 MHz, CDCl₃): δ 7.84 (s, 1H), 7.20-7.48 (m, 8H), 7.43 (s,1H), 6.84 (d, 1H, J=7.5 Hz), 5.25 (s, 2H), 3.40 (ABq, 2H, J_(AB)=9.8 Hz,Δν_(AB)=17 Hz).

Example 465,6-Dichloro-1-methoxymethyl-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (44.6 mg, 1.1153 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (200 mg, 0.7435mmol) in DMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C.for half hour. Bromomethyl methyl ether (139.4 mg, 0.09 ml, 1.1153 mmol)was added at 0° C. The reaction temperature was raised to 25° C. andstirred for 18 hours. NH₄Cl (aq.) was added and extracted with EtOAc.The organic layer was washed with brine, then dried over anhydrousMgSO₄. Solvent was distilled out under reduced pressure. Columnchromatography (silica gel, EtOAc/hexanes 0% to 30%) yielded the titlecompound as a brown solid.

MS m/z (M+H) 232

Example 475,6-Dichloro-1-methylsulfanylmethyl-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (44.6 mg, 1.1153 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (200 mg, 0.7435mmol) in DMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C.for half hour. Chloromethyl methyl sulfide (108 mg, 0.092 ml, 1.1153mmol) was added at 0° C. The reaction temperature was raised to 25° C.and the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) was addedand the reaction mixture was extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. Solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes 0% to 30%) yield the title compound as a yellow solid.

MS m/z (M+H) 329, (M−H) 327

Example 485,6-Dichloro-1-methanesulfonylmethyl-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

Oxone® (614.8 mg, 1 mmol) was dissolved in water (10 ml) and the pH wasadjusted to pH7 with NaHCO₃. To the solution was then addedtetrabutylammonium hydrogen sulfate (20 mg). The resulting solution wasadded at room temperature to a solution of5,6-dichloro-1-methylsulfanylmethyl-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole,prepared as in Example 47, (109.6 mg, 0.33 mmol) in EtOAc (4 mL). TheOxone® solution (608.87 mg) was added until the reaction completed. Theresulting mixture was washed with 1N NaOH, then extracted with EtOAc.The organic layer was washed with 15% NaCl, dried over MgSO₄ and thesolvent was distilled under reduced pressure to yield the title compoundas a yellow solid.

MS m/z (M+H) 361

Example 491-(4-Bromo-phenyl)-2-[5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-ethanone

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2,4′-dibromoacetophenone (417 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) was addedand the reaction mixture was extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes 0% to 55%) yielded the title compound as a yellow solid.

MS m/z (M−H) 464.

Example 501-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-butan-2-one

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 1-bromo-2-butanone (226.5 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and the reaction mixture was then stirred for 18 hours. NH₄Cl (aq.) wasadded and the reaction mixture was extracted with EtOAc. The organiclayer was washed with brine, then dried over anhydrous MgSO₄. Thesolvent was distilled out under reduced pressure. Column chromatography(silica gel, EtOAc/hexanes 0% to 55%) yielded the title compound as anoff-white solid.

MS m/z (M+H) 339.

Example 511-(4-Chloro-phenyl)-2-[5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-ethanone

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-bromo-4′-chloroacetophenone (350.25 mg, 1.5 mmol) was then addedto the reaction mixture at 0° C. The reaction temperature was raised to25° C. and the reaction mixture was then stirred for 18 hours. NH₄Cl(aq.) was added and the reaction mixture was extracted with EtOAc. Theorganic layer was washed with brine, then dried over anhydrous MgSO₄.The solvent was distilled out under reduced pressure. Columnchromatography (silica gel, EtOAc/hexanes 0% to 60%) yielded the titlecompound as a cream-colored solid.

MS m/z (M+H) 421, (M−H) 419.

Example 522-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(3-methoxy-phenyl)-ethanone

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-bromo-3′-methoxyacetophenone (343.5 mg, 1.5 mmol) was then addedto the reaction mixture at 0° C. The reaction temperature was raised to25° C. and the reaction mixture was then stirred for 18 hours. NH₄Cl(aq.) was added and the reaction mixture was extracted with EtOAc. Theorganic layer was washed with brine, then dried over anhydrous MgSO₄.The solvent was distilled out under reduced pressure. Columnchromatography (silica gel, EtOAc/hexanes 0% to 60%) yielded the titlecompound as a yellow solid.

MS m/z (M−H) 415.

Example 532-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-pyridin-3-yl-ethanone

NaH (60%) (120 mg, 3 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole) (269 mg, 1 mmol)in DMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. forhalf hour. 2-bromo-1-pyridin-3-ylethan-1-one hydrobromide (421.43 mg,1.5 mmol) was then added to the reaction mixture at 0° C. The reactiontemperature was raised to 25° C. and the reaction mixture was thenstirred for 18 hours. NH₄Cl (aq.) was added and the reaction mixture wasthen extracted with EtOAc. The organic layer was washed with brine, thendried over anhydrous MgSO₄. The solvent was distilled out under reducedpressure. Column chromatography (silica gel, EtOAc/hexanes 30% to 100%)yielded the title compound as an off-white solid.

MS m/z (M−H) 386.

Example 542-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(5-pyridin-2-yl-thiophen-2-yl)-ethanone

NaH (60%) (60 mg, 1,5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-bromo-1-[5-(2-pyridinyl)-2-thienyl]-1-ethanone (423.24 mg, 1.5mmol) was then added to the reaction mixture at 0° C. The reactiontemperature was raised to 25° C. and the reaction mixture was thenstirred for 18 hours. NH₄Cl (aq.) was added and the reaction mixture wasthen extracted with EtOAc. The organic layer was washed with brine, thendried over anhydrous MgSO₄. The solvent was distilled out under reducedpressure. Column chromatography (silica gel, EtOAc/hexanes 50% to 100%)yielded the title compound as a yellow solid. MS m/z (M−H) 468.

Example 552-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(2-methoxy-phenyl)-ethanone

NaH (60%) (60 mg, 1,5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-bromo-2′-methoxy-acetophenone (350.25 mg, 1.5 mmol) was thenadded to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes 5% to 60%) to yield the title compound as a yellow solid.

MS m/z (M−H) 415.

Example 562-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-thiophen-2-yl-ethanone

NaH (60%) (60 mg, 1,5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole) (269 mg, 1 mmol)in DMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. forhalf hour. 2-bromo-1-(2-thienyl)-1-ethanone (307.5 mg, 1.5 mmol) wasthen added to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and the reaction mixture was extracted with EtOAc.The organic layer was washed with brine, then dried over anhydrousMgSO₄. The solvent was distilled out under reduced pressure. Columnchromatography (silica gel, EtOAc/hexanes 0% to 60%) yielded the titlecompound as a brown solid.

MS m/z (M+H) 393, (M−H) 391.

Example 572-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-pyridin-2-yl-ethanone

NaH (60%) (120 mg, 3 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-bromo-1-(2-pyridiny)-1-ethanone hydrobromide (421.4 mg, 1.5mmol) was then added to the reaction mixture at 0° C. The reactiontemperature was raised to 25° C. and then the reaction mixture wasstirred for 18 hours. NH₄Cl (aq.) was added and extracted with EtOAc.The organic layer was washed with brine, then dried over anhydrousMgSO₄. The solvent was distilled out under reduced pressure. Columnchromatography (silica gel, EtOAc/hexanes 0% to 70%) yielded the titlecompound as a yellow solid.

MS m/z (M+H) 388, (M−H) 386.

Example 582-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(3-nitro-phenyl)-ethanone

NaH (60%) (60 mg, 1,5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-bromo-3′ nitroacetophenone (366 mg, 1.5 mmol) was then added tothe reaction mixture at 0° C. The reaction temperature was raised to 25°C. and the reaction mixture was then stirred for 18 hours. NH₄Cl (aq.)was added and extracted with EtOAc. The organic layer was washed withbrine, then dried over anhydrous MgSO₄. The solvent was distilled outunder reduced pressure. Column chromatography (silica gel, EtOAc/hexanes0% to 70%) yielded the title compound as a light brown solid.

MS m/z (M−H) 430.

Example 592-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(4-nitro-phenyl)-ethanone

NaH (60%) (60 mg, 1,5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-bromo-4′ nitroacetophenone (366 mg, 1.5 mmol) was then added tothe reaction mixture at 0° C. The reaction temperature was raised to 25°C. and the reaction mixture was then stirred for 18 hours. NH₄Cl (aq.)was added and the reaction mixture was extracted with EtOAc. The organiclayer was washed with brine, then dried over anhydrous MgSO₄. Thesolvent was distilled out under reduced pressure. Column chromatography(silica gel, EtOAc/hexanes 0% to 70%) yielded the title compound as alight brown solid.

MS m/z (M+H) 432, (M−H) 430.

Example 601-Benzyl-5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1,5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. Benzyl bromide (256.5 mg, 1.5 mmol) was then added to the reactionmixture at 0° C. The reaction temperature was raised to 25° C. and thenthe reaction mixture was stirred for 18 hours. NH₄Cl (aq.) was added andextracted with EtOAc. The organic layer was washed with brine, thendried over anhydrous MgSO₄. The solvent was distilled out under reducedpressure. Column chromatography (silica gel, EtOAc/hexanes 0% to 40%)yielded the title compound as a light brown solid.

MS m/z (M+H) 359, (M−H) 357.

Example 615,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1-(4-trifluoromethyl-benzyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1,5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 4-(trifluoromethyl)-benzyl bromide (358.5 mg, 1.5 mmol) was thenadded to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes 0% to 50%) yielded the title compound as an off-whitesolid.

MS m/z (M+H) 427.

Example 625,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1,5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 4-(trifluoromethoxy)-benzyl bromide (382.5 mg, 1.5 mmol) was thenadded to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes 0% to 60%) yielded the title compound as a brown solid.

MS m/z (M+H) 443.

Example 635,6-Dichloro-1-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (120 mg, 3 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-(bromomethyl)-pyridine hydrobromide (379.5 mg, 1.5 mmol) wasthen added to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes 30% to 100%) yielded the title compound as a yellow solid.

MS m/z (M+H) 360.

Example 642-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone

NaH (60%) (60 mg, 1,5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone-1-one (385.5mg, 1.5 mmol) was then added to the reaction mixture at 0° C. Thereaction temperature was raised to 25° C. and then the reaction mixturewas stirred for 18 hours. NH₄Cl (aq.) was added and extracted withEtOAc. The organic layer was washed with brine, then dried overanhydrous MgSO₄. The solvent was distilled out under reduced pressure.The residue was triturated with DCM to yield the title compound as ayellow solid.

MS m/z (M−H) 443.

Example 655,6-Dichloro-1-pyridin-4-ylmethyl-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (120 mg, 3 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (269 mg, 1 mmol) inDMF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 4-(bromomethyl)-pyridine hydrobromide (379.5 mg, 1.5 mmol) wasthen added to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes (30% to 100%) yielded the title compound as a white solid.

MS m/z (M+H) 360.

Example 663-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-ylmethyl]-benzonitrile

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. α-bromo-m-tolunitrile (294 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and then the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) wasadded and extracted with EtOAc. The organic layer was washed with brine,then dried over anhydrous MgSO₄. The solvent was distilled out underreduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0%to 60%) yielded the title compound as an off-white solid.

MS m/z (M+H) 384; (M−H) 382.

Example 672-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-ylmethyl]-benzonitrile

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. α-bromo-o-tolunitrile (294 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and then the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) wasadded and extracted with EtOAc. The organic layer was washed with brine,then dried over anhydrous MgSO₄. The solvent was distilled out underreduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0%to 60%) yielded the title compound as an off-white solid.

MS m/z (M+H) 384.

Example 682-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-1-(5-methyl-3-Phenyl-isoxazol-4-yl)-ethanone

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhours. 2-bromo-1-(5-methyl-3-phenylisoxazol-4-yl)ethan-1-one (420 mg,1.5 mmol) was then added to the reaction mixture at 0° C. The reactiontemperature was raised to 25° C. and then the reaction mixture wasstirred for 18 hours. NH₄Cl (aq.) was added and extracted with EtOAc.The organic layer was washed with brine, then dried over anhydrousMgSO₄. The solvent was distilled out under reduced pressure. Columnchromatography (silica gel, EtOAc/hexanes (0% to 60%) yielded the titlecompound as a white solid.

MS m/z (M+H) 466.

Example 694-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-ylmethyl]-benzonitrile

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. α-bromo-p-tolunitrile (294 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and then the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) wasadded and extracted with EtOAc. The organic layer was washed with brine,then dried over anhydrous MgSO₄. The solvent was distilled out underreduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0%to 60%) yielded the title compound as a brown solid.

MS m/z (M−H) 381.

Example 705,6-Dichloro-1-(2-fluoro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-fluorobenzyl bromide (283.5 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and then the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) wasadded and extracted with EtOAc. The organic layer was washed with brine,then dried over anhydrous MgSO₄. The solvent was distilled out underreduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0%to 60%) yielded the title compound as a light yellow solid.

MS m/z (M+H) 377.

Example 715,6-Dichloro-1-(3-fluoro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 3-fluorobenzyl bromide (283.5 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and then the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) wasadded and extracted with EtOAc. The organic layer was washed with brine,then dried over anhydrous MgSO₄. The solvent was distilled out underreduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0%to 60%) yielded the title compound as an off-white solid.

MS m/z (M+H) 377.

Example 725,6-Dichloro-1-(3-chloro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 3-chlorobenzyl bromide (308.25 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and then the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) wasadded and extracted with EtOAc. The organic layer was washed with brine,then dried over anhydrous MgSO₄. The solvent was distilled out underreduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0%to 60%) yielded the title compound as a yellow solid.

MS m/z (M+H) 393.

Example 735,6-Dichloro-1-(4-chloro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 4-chlorobenzyl bromide (308.25 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and then the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) wasadded and extracted with EtOAc. The organic layer was washed with brine,then dried over anhydrous MgSO₄. The solvent was distilled out underreduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0%to 60%) yielded the title compound as a yellow solid.

MS m/z (M−H) 393.

Example 745,6-Dichloro-1-(2-chloro-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 2-chlorobenzyl bromide (283.5 mg, 1.5 mmol) was then added to thereaction mixture at 0° C. The reaction temperature was raised to 25° C.and then the reaction mixture was stirred for 18 hours. NH₄Cl (aq.) wasadded and extracted with EtOAc. The organic layer was washed with brine,then dried over anhydrous MgSO₄. The solvent was distilled out underreduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0%to 60%) yielded the title compound as an off-white solid.

MS m/z (M+H) 393.

Example 755,6-Dichloro-1-(4-pyrazol-1-yl-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 1-[4-(bromomethyl)-phenyl]-1H-pyrazole (356 mg, 1.5 mmol) was thenadded to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes (0% to 60%) yielded the title compound as a yellow solid.

MS m/z (M+H) 425.

Example 765,6-Dichloro-1-(4-[1,2,3]thiadiazol-4-yl-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 4-[4-(bromomethyl)-phenyl]-1,2,3-thiazole (382.7 mg, 1.5 mmol) wasthen added to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes (0% to 60%) yielded the title compound as a yellow solid.MS m/z (M+H) 443.

Example 775,6-Dichloro-1-(5-methyl-isoxazol-4-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 3-(bromomethyl)-5-methylisoxazole (264 mg, 1.5 mmol) was thenadded to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes (0% to 60%) yielded the title compound as a yellow solid.

MS m/z (M−H) 363.

Example 785,6-Dichloro-1-(4-pyrrol-1-yl-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (60 mg, 1.5 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (269 mg, 1 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 1-[4-(bromomethyl)phenyl]-1H-pyrrol (354 mg, 1.5 mmol) was thenadded to the reaction mixture at 0° C. The reaction temperature wasraised to 25° C. and then the reaction mixture was stirred for 18 hours.NH₄Cl (aq.) was added and extracted with EtOAc. The organic layer waswashed with brine, then dried over anhydrous MgSO₄. The solvent wasdistilled out under reduced pressure. Column chromatography (silica gel,EtOAc/hexanes (0% to 70%) yielded the title compound as a yellow solid.

¹H-NMR (300 Hz, d₆ _(—) DMSO) δ 4.26 (ABq, 2H, J_(AB)=10.7 Hz,Δν_(AB)=18 Hz), 5.65 (s, 2H), 6.24 (t, 2H, J=2.1 Hz), 7.20 (d, 2H, J=8.6Hz), 7.34 (t, 2H, J=2.2 Hz), 7.55 (d, 2H, J=8.6 Hz), 7.90 (s, 1H), 8.02(s, 1H).

Example 791-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-butan-2-oneoxime

1-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]butan-2-one(339 mg, 1 mmol), hydroxylamine hydrochloride (227.5 mg, 3.25 mmol) andpyridine (3 mL) in ethanol (3 mL) were heated to 70° C. for 5 hours. Thereaction mixture was then poured into water and extracted with EtOAc.The organic layer was washed with 15% NaCl, brine, then dried overanhydrous MgSO₄. The solvent was distilled out under reduced pressure.Column chromatography (silica gel, EtOAc/hexanes (0% to 60%) yielded thetitle compound as a white solid.

MS m/z (M−H) 354.

Example 801-(4-Benzyloxy-benzyl)-5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (120 mg, 3 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (538 mg, 2 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 4-benzyloxy-benzyl chloride (698 mg, 3 mmol) and potassium iodide(498 mg, 3 mmol) were then added to the reaction mixture at 0° C. Thereaction temperature was raised to 25° C. and then the reaction mixturewas stirred for 18 hours. NH₄Cl (aq.) was added and extracted withEtOAc. The organic layer was washed with brine, then dried overanhydrous MgSO₄. The solvent was distilled out under reduced pressure.Column chromatography (silica gel, EtOAc/hexanes (0% to 70%) yielded thetitle compound as a yellow solid.

MS m/z (M−H) 463.

Example 815,6-Dichloro-1-(4-methoxy-benzyl)-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) (120 mg, 3 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (538 mg, 2 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 4-methoxy-benzyl chloride (470 mg, 3 mmol) and potassium iodide(498 mg, 3 mmol) were then added to the reaction mixture at 0° C. Thereaction temperature was raised to 25° C. and then the reaction mixturewas stirred for 18 hours. NH₄Cl (aq.) was added and extracted withEtOAc. The organic layer was washed with brine, then dried overanhydrous MgSO₄. The solvent was distilled out under reduced pressure.Column chromatography (silica gel, EtOAc/hexanes (0% to 70%), solventwas distilled under reduced pressure and the residue was dissolved inDCM. The resulting solution was diluted with hexane. The precipitate wasfiltered and dried to yield the title compound as an off-white solid.

MS m/z (M+H) 389; (M−H) 387.

Example 821-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-butan-2-ol

Sodium borohydride (11.16 mg, 0.2949 mmol) was added into methanol (5mL). After the bubbling ceased,1-[5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-butan-2-one(19170-168) (100 mg, 0.2949 mmol) was added. The resulting mixture wasstirred at room temperature for 1 hour. The resulting mixture was pouredinto water and then extracted with EtOAc. The organic layer was driedover anhydrous MgSO₄. The solvent was distilled out under reducedpressure to yield the title compound as an off-white solid.

MS m/z (M+H) 341.

Example 831-(4-Bromo-benzyl)-5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) 120 mg, 3 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (538 mg, 2 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. 4-bromo-benzyl bromide (749.8 mg, 3 mmol) and potassium iodide(498 mg, 3 mmol) were then added to the reaction mixture at 0° C. Thereaction temperature was raised to 25° C. and then the reaction mixturewas stirred for 18 hours. NH₄Cl (aq.) was added and then the reactionmixture was extracted with EtOAc. The organic layer was washed withbrine, then dried over anhydrous MgSO₄. Solvent was distilled out underreduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0%to 60%) yielded the title compound as a solid light brown solid.

MS m/z (M+H) 438.

Example 844-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-ylmethyl]-benzoicacid ethyl ester

NaH (60%) 120 mg, 3 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (538 mg, 2 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. Ethyl 4-(bromomethyl)-benzoate (729.3 mg, 3 mmol) and potassiumiodide (498 mg, 3 mmol) were then added to the reaction mixture at 0° C.The reaction temperature was raised to 25° C. and then the reactionmixture was stirred for 18 hours. NH₄Cl (aq.) was added and extractedwith EtOAc. The organic layer was washed with brine, then dried overanhydrous MgSO₄. The solvent was distilled out under reduced pressure.Column chromatography (silica gel, EtOAc/hexanes (0% to 60%) yielded thetitle compound as an off-white solid.

¹H-NMR (300 Hz, d₆-DMSO) δ 1.29 (t, 3H, J=7.1 Hz), 4.22 (ABq, 2H,J_(AB)=10.6 Hz, Δν_(AB)=18.4 Hz), 4.29 (q, 2H, J=7.1 Hz), 5.75 (s, 2H),7.20 (d, 2H, J=8.3 Hz), 7.84 (s, 1H), 7.92 (d, 2H, J=8.4 Hz), 8.03 (s,1H).

Example 851-(2-Bromo-benzyl)-5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

NaH (60%) 120 mg, 3 mmol) was added into a solution ofdichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole.5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-indole (538 mg, 2 mmol) in DMF(5 ml) at 0° C. The resulting mixture was stirred at 0° C. for halfhour. Ethyl 4-(bromomethyl)-benzoate (729.3 mg, 3 mmol) and potassiumiodide (498 mg, 3 mmol) were then added to the reaction mixture at 0° C.The reaction temperature was raised to 25° C. and then the reactionmixture was stirred for 18 hours. NH₄Cl (aq.) was added and extractedwith EtOAc. The organic layer was washed with brine, then dried overanhydrous MgSO₄. The solvent was distilled out under reduced pressure.Column chromatography (silica gel, EtOAc/hexanes (0% to 60%) yielded thetitle compound as a white solid.

MS m/z (M+H) 439.

Example 861-(5,6-Dimethyl-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

4,5-Dimethyl-benzene-1,2-diamine (5.04 g; 37.0 mmoles) and3,3,3-trifluoro-2-hydroxy-propionic acid (8.01 g; 55.6 mmoles) weresuspended in 6N HCl (9 mL; 54 mmoles) under a nitrogen atmosphere. Thereaction was stirred vigorously and heated to 108° C. for 18 hrs, thencooled to room temperature. The reaction was diluted with water (100 mL)and with ethyl acetate (100 mL), then sodium bicarbonate (6.90 g; 81.00mmoles) was added slowly and in portions to quench the reaction. Theaqueous layer was separated and extracted with ethyl acetate (3×40 mL).The extracts were combined, washed with water (30 mL) and brine (30 mL),then dried over Na₂SO₄. The filtrate was concentrated in vacuo to yielda crude brown solid which was purified by column chromatography (SiO₂;30% ethyl acetate/CH₂Cl₂) to yield the title compound as an off-whitesolid.

¹H NMR (400 MHz, CD₃CN) δ 10.51 (br s, 1H), δ 7.37 (br d, 2H), δ 5.36(q, J=6.9 Hz, 1H), δ 5.16 (br s, 1H), δ 2.35 (s, 6H).

MS calculated for C₁₁H₁₁F₃N₂O: 244.08

MS Measured: 245 (M+H); 243 (M−H).

Example 871-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

4-Chloro-5-fluoro-benzene-1,2-diamine (5.20 g; 32.4 mmoles) and3,3,3-trifluoro-2-hydroxy-propionic acid (7.00 g; 48.6 mmoles) weresuspended in 6N HCl (9 mL; 54 mmoles) under a nitrogen atmosphere. Thereaction was stirred vigorously and heated to 108° C. for 18 hrs, thencooled to room temperature. The reaction was diluted with water (100 mL)and with ethyl acetate (100 mL), then sodium bicarbonate (6.90 g; 81.00mmoles) was added slowly and in portions to quench the reaction. Theaqueous layer was separated and extracted with ethyl acetate (3×40 mL).The extracts were combined, washed with water (30 mL) and brine (30 mL),then dried over Na₂SO₄. The filtrate was concentrated in vacuo to yielda crude brown solid which was then purified by column chromatography(SiO₂; 30% ethyl acetate/CH₂Cl₂) to yield the title compound as anoff-white solid.

¹H NMR (400 MHz, CD₃CN) δ 7.74 (d, J=6.7 Hz, 1H), δ 7.49 (d, J=9.5, 1H),δ 5.41 (q, J=6.8 Hz, 1H), δ 5.16 (br s, 1H), δ 2.35 (s, 6H)

MS calculated for C₉H₅ClF₄N₂O: 268.00

MS measured: 269 (M+H); 267 (M−H).

Example 881-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanone

1-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanol(0.34 g; 1.3 mmoles), 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxyfree radical (4-methoxy-TEMPO free radical; 6.1 mg; 0.03 mmoles) andpotassium bromide (KBr; 18 mg; 0.15 mmoles) were dissolved in THF (3.5mL). The reaction mixture was stirred while cooled to −10° C., after 10min. a sodium hypochlorite solution (bleach; 10-13% aqueous; 3.0 mL;5.04 mmoles) was added and allowed to stir for 15 min., then warmed toroom temperature and stirred for 15 min. The reaction mixture wasdiluted with water (20 mL) and ethyl acetate (30 mL), the layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×30mL). The extracts were combined and washed with water (30 mL) and brine(40 mL), then dried over Na₂SO₄. The filtrate was concentrated in vacuoand purified by column chromatography (SiO₂; 100% diethyl ether) toyield the title compound as a light yellow solid.

¹H NMR (400 MHz, CD₃CN) δ 7.83 (d, J=6.7 Hz, 1H), δ 7.77 (d, J=9.5 Hz,1H)

MS calculated for C₉H₃ClF₄N₂O: 265.99

MS Measured: 265, 267 (M−H).

Example 891-(5,6-Difluoro-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

4,5-Difluoro-benzene-1,2-diamine (4.98 g; 34.5 mmoles) and3,3,3-trifluoro-2-hydroxy-propionic acid (7.48 g; 51.9 mmoles) weresuspended in 6N HCl (8 mL; 48 mmoles) under a nitrogen atmosphere. Thereaction was stirred vigorously and heated to 108° C. for 18 hrs, thencooled to room temperature. The reaction was diluted with water (100 mL)and with ethyl acetate (100 mL), then sodium bicarbonate (6.05 g; 72.0mmoles) was added slowly and in portions to quench the reaction. Theaqueous layer was separated and extracted with ethyl acetate (3×40 mL).The extracts were combined, washed with water (30 mL) and brine (30 mL),then dried over Na₂SO₄. The filtrate was concentrated in vacuo to yielda crude brown solid which was then purified by column chromatography(SiO₂; 30% ethyl acetate/CH₂Cl₂) to yield the title compound as a paleorange solid.

¹H NMR (400 MHz, CD₃CN) δ 7.35 (m, 1H), δ 7.21 (m, 1H), δ 5.44 (q, J=6.8Hz, 1H)

MS calculated for C₉H₅F₅N₂O: 252.03

MS measured: 253 (M+H); 251 (M−H).

Example 901-(5,6-DiChloro-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

4,5-Dichloro-benzene-1,2-diamine (8.50 g; 48.0 mmoles) and3,3,3-trifluoro-2-hydroxy-propionic acid (10.59 g; 73.52 mmoles) weresuspended in 6N HCl (19 mL; 114 mmoles) under a nitrogen atmosphere. Thereaction was stirred vigorously and heated to 108° C. for 18 hrs, thencooled to room temperature. The reaction was diluted with water (200 mL)and with ethyl acetate (200 mL), then sodium bicarbonate (6.05 g; 72.0mmoles) was added slowly and in portions to quench the reaction. Theaqueous layer was separated and extracted with ethyl acetate (3×80 mL).The extracts were combined, washed with water (60 mL) and brine (60 mL),then dried over Na₂SO₄. The filtrate was concentrated in vacuo to yielda crude brown solid which was then purified by column chromatography(SiO₂; 30% ethyl acetate/CH₂Cl₂) to yield the title compound as a brownsolid.

¹H NMR (400 MHz, CD₃CN) δ 7.80 (s, 2H), δ 5.43 (q, J=6.8 Hz, 1H)

MS calculated for C₉H₅Cl₂F₃N₂O: 283.97

MS measured: 285, 287 (M+H); 283, 285 (M−H).

Example 91 Diastereomers of 3,3,3-Trifluoro-2-methoxy-2-phenyl-propionicacid1-(5,6-dichloro-1H-benzamidazol-2-yl)-2,2,2-trifluoro-1-methyl-ethylester

2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-propan-2-ol (2.24g; 7.86 mmoles) was dissolved in pyridine (1.4 mL; 17 mmoles) and THF(20 mL), then stirred under a nitrogen atmosphere.(R)-(−)-α-Methoxy-α-(trifluoromethyl)phenylacetyl chloride (1.85 mL;9.91 mmoles) was added to the reaction mixture and stirred at roomtemperature for 18 hrs. The reaction mixture was concentrated in vacuo,and then dissolved in 50% diethyl ether/ethyl acetate (50 mL), thenwashed with water (30 mL). The aqueous layer was extracted with 50%diethyl ether/ethyl acetate (3×50 mL), the extracts were combined,washed with water (30 mL), brine (50 mL) and dried over Na₂SO₄. Thefiltrate was concentrated in vacuo then purified by columnchromatography (SiO₂; 100% CH₂Cl₂) to yield the title compound as ayellow oil, as a mixture of diasteriomers. The diasteriomeric mixturewas separated by chiral chromatography (Chiralpak AD; 30%isopropanol/heptane), to yield a white foam (peak 1; retention time:9.04 min. (@ 100 mL/min)) and an off white solid (peak 2; retentiontime: 19.04 min. (@100 ml/min)).

Peak 1:

¹H NMR (300 MHz, CD₃CN) δ 11.19 (br s, 1H), δ 7.87 (br s, 1H), δ 7.77(br s, 1H), δ 7.51-7.37 (series of m, 5H), δ 6.76 (q, J=6.4, 1H), δ 3.61(s, 3H)

MS calculated for C₁₉H₁₂Cl₂F₆N₂O₃: 500.01

MS measured: 501, 503 (M+H); 499, 501 (M−H).

[α]_(D) ²⁰=−22; c=0.306 in methanol.

Peak 2

¹H NMR (300 MHz, CD₃CN) δ 11.18 (br s, 1H), δ 7.91-7.81 (br m, 2H), δ7.58-7.45 (series of m, 5H), δ 6.78 (q, J=6.3, 1H), δ 3.53 (s, 3H)

MS calculated for C₁₉H₁₂Cl₂F₆N₂O₃: 500.01

MS measured: 501, 503 (M+H); 499, 501 (M−H)

[α]_(D) ²⁰=−49; c=0.314 in methanol.

Example 921-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanol (0.29 g;1.00 mmole), 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy free radical(4-methoxy-TEMPO free radical; 4.4 mg; 0.03 mmoles) and potassiumbromide (KBr; 13 mg; 0.11 mmoles) were dissolved in THF (2.9 mL). Thereaction mixture was stirred while cooled to −10° C., after 10 min. asodium hypochlorite solution (bleach; 10-13% aqueous; 2.10 mL; 3.53mmoles) was added and allowed to stir for 15 min., then warmed to roomtemperature and stirred for 15 min. The reaction mixture was dilutedwith water (20 mL) and ethyl acetate (30 mL), the layers were separatedand the aqueous layer was extracted with ethyl acetate (3×30 mL). Theextracts were combined and washed with water (30 mL) and brine (40 mL),then dried over Na₂SO₄. The filtrate was concentrated in vacuo andpurified by column chromatography (SiO₂; 100% ether) to yield the titlecompound as a light yellow solid.

¹H NMR (400 MHz, CD₃CN) δ 8.01 (s, 1H), δ 7.83 (br s, 2H)

MS calculated for C₉H₃Cl₂F₃N₂O: 281.96

MS measured: 281, 283 (M−H).

Example 931-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ehtanone oxime

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.3005g; 1.062 mmoles) and hydroxylamine hydrochloride (0.2389 g, 3.438mmoles) were suspended in pyridine (3 mL) and ethanol (3 mL), thenheated to 70° C. for 3 hrs. The reaction mixture was cooled to roomtemperature, water was water (50 mL) and the reaction mixture was thenextracted with ethyl acetate (3×40 ml). The extracts were combined thenwashed with water (20 mL), brine (30 mL) and dried over Na₂SO₄. Thefiltrate was concentrated in vacuo and purified by column chromatography(SiO₂; 30% ethyl acetate/CH₂Cl₂) to yield the title compound as anoff-white solid, as a mixture of oxime E and Z isomers.

¹H NMR (400 MHz, d₆-DMSO) δ 8.33-7.64 (series of s, 2H)

MS calculated for C₉H₄Cl₂F₃N₂O: 296.96

MS measured: 296, 298 (M−H).

Example 941-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

4-Chloro-5-methyl-benzene-1,2-diamine (5.06 g; 32.3 mmoles) and3,3,3-trifluoro-2-hydroxy-propionic acid (7.11 g; 49.4 mmoles) weresuspended in 6N HCl (12 mL; 72 mmoles) under a nitrogen atmosphere. Thereaction was stirred vigorously and heated to 108° C. for 18 hrs, thencooled to room temperature. The reaction was diluted with water (100 mL)and with ethyl acetate (100 mL), then sodium bicarbonate (9.12 g; 109mmoles) was added slowly and in portions to quench the reaction. Theaqueous layer was separated and extracted with ethyl acetate (3×40 mL).The extracts were combined, washed with water (30 mL) and brine (30 mL),then dried over Na₂SO₄. The filtrate was concentrated in vacuo to yielda crude brown solid which was then purified by column chromatography(SiO₂; 30% ethyl acetate/CH₂Cl₂) to yield the title compound as apurple/brown solid.

¹H NMR (400 MHz, CD₃CN) δ 7.65 (s, 1H), δ 7.52 (s, 1H), δ 5.40 (q, J=6.9Hz, 1H), δ 2.46 (s, 3H)

MS calculated for C₁₀H₈ClF₃N₂O: 264.03

MS measured: 265, 267 (M+H); 263, 265 (M−H).

Example 951-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanone

1-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanol(0.33 g; 1.2 mmole), 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy freeradical (4-methoxy-TEMPO free radical; 5.6 mg; 0.03 mmoles) andpotassium bromide (KBr; 22 mg, 0.18 mmoles) were dissolved in THF (3.5mL). The reaction mixture was stirred while cooled to −10° C. after 10min. a sodium hypochlorite solution (bleach; 10-13% aqueous; 3.0 mL; 5.0mmoles) was added and the reaction mixture was allowed to stir for 15min., then warmed to room temperature and stirred for 15 min. Thereaction mixture was diluted with water (20 mL) and ethyl acetate (30mL), the layers were separated and the aqueous layer was extracted withethyl acetate (3×30 mL). The extracts were combined and washed withwater (30 mL) and brine (40 mL), then dried over Na₂SO₄. The filtratewas concentrated in vacuo and then purified by column chromatography(SiO₂; 100% diethyl ether) to yield the title compound as a white solid.

¹H NMR (400 MHz, CD₃CN) δ 7.86 (br s, 1H), δ 7.69 (br s, 1H), δ 7.54 (brs, 1H), δ 2.47 (s, 3H)

MS calculated for C₁₀H₆ClF₃N₂O: 262.01

MS measured: 261, 263 (M−H).

Example 96 1-(5-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

4-Chloro-benzene-1,2-diamine (2.02 g; 14.2 mmoles) and3,3,3-trifluoro-2-hydroxy-propionic acid (3.10 g; 21.5 mmoles) weresuspended in 6N HCl (5 mL; 30 mmoles) and water (4 mL) under a nitrogenatmosphere. The reaction was stirred vigorously and heated to 108′C for18 hrs, then cooled to room temperature. The reaction was diluted withwater (400 mL) and with ethyl acetate (500 mL), then sodium bicarbonate(3.83 g; 45.6 mmoles) was added slowly and in portions to quench thereaction. The aqueous layer was separated and extracted with ethylacetate (3×30 mL). The extracts were combined, washed with water (30 mL)and brine (30 mL), then dried over Na₂SO₄. The filtrate was concentratedin vacuo to yield a crude brown solid which was then purified by columnchromatography (SiO₂; 30% ethyl acetate/CH₂Cl₂) to yield the titlecompound as a tan solid.

¹H NMR (400 MHz, CD₃CN) δ 7.65 (n d, J=1.5, 1H), δ 7.58 (d, J=8.6, 1H),δ 7.27 (dd, J=6.6, 2.0, 3H) δ 5.42 (q, J=6.9 Hz, 1H)

MS calculated for C₉H₆ClF₃N₂O: 250.01

MS measured: 251, 253 (M+H); 249, 251 (M−H).

Example 972-(2,2,2-Trifluoro-1-hydroxy-ethyl)-6-trifluoromethyl-1H-benzoimdazole-5-carbonitrile

4,5-Diamino-2-trifluoromethyl-benzonitrile (4.14 g; 20.6 mmoles) and3,3,3-trifluoro-2-hydroxy-propionic acid (4.50 g; 31.2 mmoles) weresuspended in 6N HCl (7 mL; 42 mmoles) under a nitrogen atmosphere. Thereaction was stirred vigorously and heated to 108° C. for 18 hrs, thencooled to room temperature. The reaction was diluted with water (100 mL)and with ethyl acetate (100 mL), then sodium bicarbonate (5.19 g; 62.0mmoles) was added slowly and in portions to quench the reaction. Theaqueous layer was separated and extracted with ethyl acetate (3×40 mL).The extracts were combined, washed with water (30 mL) and brine (30 mL),then dried over Na₂SO₄. The filtrate was concentrated in vacuo to yielda crude dark solid which was then purified by column chromatography(SiO₂; 30% ethyl acetate/CH₂Cl₂) to yield the title compound as a darkbrown solid.

¹H NMR (400 MHz, CD₃CN) δ 8.27 (s, 1H), δ 8.14 (s, 1H), δ 5.54 (q, J=6.9Hz, 1H)

MS calculated for C₁₁H₅F₆N₃O: 309.03

MS measured: 310 (M+H); 308 (M−H).

Example 98 1-(5,6-Dinitro-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

4,5-Dinitro-benzene-1,2-diamine (2.01 g; 10.2 mmoles) and3,3,3-trifluoro-2-hydroxy-propionic acid (2.22 g; 15.4 mmoles) weresuspended in 6N HCl (5 mL; 30 mmoles) and water (4 mL) under a nitrogenatmosphere. The reaction was stirred vigorously and heated to 108′C for18 hrs, then cooled to room temperature. The reaction was diluted withwater (40 mL) and with ethyl acetate (40 mL), then sodium bicarbonate(3.79 g; 45.0 mmoles) was added slowly and in portions to quench thereaction. The aqueous layer was separated and extracted with ethylacetate (3×30 mL). The extracts were combined, washed with water (30 mL)and brine (40 mL), then dried over Na₂SO₄. The filtrate was concentratedin vacuo to yield a crude brown solid which was then purified by columnchromatography (SiO₂; 30% ethyl acetate/CH₂Cl₂) to yield the titlecompound as a brown solid.

¹H NMR (400 MHz, CD₃CN) δ 8.29 (s, 2H), δ 5.55 (q, J=6.8, 1H)

MS calculated for C₉H₅F₃N₄O₅: 306.16

MS measured: 305 (M−H).

Example 991-(5,6-Dimethoxy-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

4,5-Dimethoxy-benzene-1,2-diamine (2.02 g; 12.0 mmoles) and3,3,3-trifluoro-2-hydroxy-propionic acid (2.67 g; 18.5 mmoles) weresuspended in 6N HCl (5 mL; 30 mmoles) and water (4 mL) under a nitrogenatmosphere. The reaction was stirred vigorously and heated to 108° C.for 18 hrs, then cooled to room temperature. The reaction was dilutedwith water (40 mL) and with ethyl acetate (40 mL), then sodiumbicarbonate (3.84 g; 46.0 mmoles) was added slowly and in portions toquench the reaction. The aqueous layer was separated and extracted withethyl acetate (3×30 mL). The extracts were combined, washed with water(30 mL) and brine (40 mL), then dried over Na₂SO₄. The filtrate wasconcentrated in vacuo to yield a crude dark orange solid which was thenpurified by column chromatography (SiO₂; 30% ethyl acetate/CH₂Cl₂) toyield the title compound as a bright orange solid.

¹H NMR (400 MHz, CD₃CN) δ 7.15 (br s, 1H), δ 7.06 (br s, 1H), δ 5.34 (q,J=6.8, 1H)

MS calculated for C₁₁H₁₁F₃N₂O₃: 267.07

MS measured: 277 (M+H); 275 (M−H).

Example 1003-(5,6-Dichloro-2-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-2-methyl-propan-2-ol

4,5-Dichloro-benzene-1,2-diamine (0.53 g; 3.0 mmoles) and4,4,4-trifluoro-3-hydroxy-3-methyl-butyric acid (0.78 g; 4.5 mmoles)were suspended in 6N HCl (4 mL; 24 mmoles) and water (4 mL) under anitrogen atmosphere. The reaction was stirred vigorously and heated to108° C. for 18 hrs, then cooled to room temperature. The reaction wasdiluted with water (25 mL) and with ethyl acetate (30 mL), then sodiumbicarbonate (7.59 g; 90.3 mmoles) was added slowly and in portions toquench the reaction. The aqueous layer was separated and extracted withethyl acetate (3×20 mL). The extracts were combined, washed with water(20 mL) and brine (20 mL), then dried over Na₂SO₄. The filtrate wasconcentrated in vacuo to yield a crude brown solid which was thenpurified by column chromatography (SiO₂; 100% CH₂Cl₂) to yield the titlecompound as a light orange solid.

¹H NMR (400 MHz, CD₃CN) δ 7.74 (s, 2H), δ 3.28 (d, J=15, 1H), δ 3.15 (d,J=15, 1H), δ 1.37 (s, 3H)

MS calculated for C₁₁H₁₉Cl₂F₃N₂O: 312.00

MS measured: 313, 315 (M+H); 311, 313 (M−H).

Example 101 5,6-Dichloro-2-(1,2,2,2-tetrafluoro-ethyl)-1H-benzoimidazole

4,5-Dichloro-benzene-1,2-diamine (2.03 g; 11.5 mmoles) and2,3,3,3-tetrafluoro-propionic acid (1.99 g; 13.6 mmoles) were suspendedin 6N HCl (5 mL; 30 mmoles) under a nitrogen atmosphere. The reactionwas stirred vigorously and heated to 108° C. for 18 hrs, then cooled toroom temperature. The reaction was diluted with water (60 mL) and withethyl acetate (60 mL), then sodium bicarbonate (4.02 g; 47.9 mmoles) wasadded slowly and in portions to quench the reaction. The aqueous layerwas separated and extracted with ethyl acetate (3×30 mL). The extractswere combined, washed with water (30 mL) and brine (30 mL), then driedover Na₂SO₄. The filtrate was concentrated in vacuo to yield a crudebrown solid. A sample of the crude brown solid was purified by columnchromatography (SiO₂; 100% CH₂Cl₂) to yield the title compound as alight orange solid.

¹H NMR (400 MHz, CD₃CN) δ 7.65 (s, 1H), δ 6.28 (dq, J=37, 6.0 Hz, 1H)

MS calculated for C₉H₅Cl₂F₄N₂: 285.97

MS measured: 287, 289 (M+H); 285, 287 (M−H).

Example 102 5,6-Dichloro-2-(pentafluoroethyl)-1H-benzoimidazole

4,5-Dichloro-benzene-1,2-diamine (2.01 g; 11.4 mmoles) and2,2,3,3,3-pentafluoro-propionic acid (1.80 mL; 17.3 mmoles) weresuspended in 6N HCl (10 mL; 60 mmoles) under a nitrogen atmosphere. Thereaction was stirred vigorously and heated to 108° C. for 18 hrs, thencooled to room temperature. The reaction was diluted with water (60 mL)and with ethyl acetate (60 mL), then sodium bicarbonate (7.59 g; 90.3mmoles) was added slowly and in portions to quench the reaction. Theaqueous layer was separated and extracted with ethyl acetate (3×30 mL).The extracts were combined, washed with water (30 mL) and brine (30 mL),then dried over Na₂SO₄. The filtrate was concentrated in vacuo to yielda crude brown solid which was then purified by column chromatography(SiO₂; 100% CH₂Cl₂) to yield the title compound as a light tan solid.

¹H NMR (400 MHz, CD₃CN) δ 7.94 (s, 2H)

MS calculated for C₉H₃Cl₂F₅N₂: 303.96

MS measured: 305, 307 (M+H); 303, 305 (M−H).

Example 1034-[5,6-Dichloro-2-(trifluoro-ethyl)-benzoimidazol-1-ylmethyl]-benzaldehyde

4-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-ylmethyl]-benzonitrile(0.4079 g; 1.0617 mmoles) was suspended in CH₂Cl₂ (3 mL), treated with1.5 M diisobutylaluminum hydride in toluene (1.42 mL; 2.13 mmoles) andstirred at room temperature for 3 hrs. The reaction mixture was quenchedwith saturated Rochelle's salt solution (1 mL) and stirred overnight,then filtered through a pad of Celite. The filtrate was diluted withethyl acetate (30 mL), washed with water (20 mL), brine and dried overNa₂SO₄. The filtrate was concentrated in vacuo and then purified bycolumn chromatography (SiO₂; 100% CH₂Cl₂) to yield the title compound asa yellow oil.

MS calculated for C₁₇H₁₁Cl₂F₃N₂O: 389.02

MS measured: 389, 387 (M+H); 385, 387 (M−H).

Example 104(+)-1-(5,6-DiChloro-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

A solution of “Peak 1” prepared as in Example 91 (136 mg; 0.27 mmoles)was suspended in a mixture of dioxane and water (10 mL, 4:1) and treatedwith NaOH (0.5 mL; 2 mmoles). The reaction was stirred vigorously andheated to 50° C. for 30 min, then cooled to room temperature. Thereaction was diluted with water (50 mL) and 1 N HCl (3 mL, 3 mmol). Theresulting white precipitate was collected by suction filtration,dissolved in ethyl acetate and then purified by flash chromatography(SiO₂, 30% ethyl acetate/dcm) to yield the title compound as a whitesolid.

¹H NMR (400 MHz, CD₃CN) δ 7.80 (s, 2H), δ 5.43 (q, J=6.8 Hz, 1H)

MS calculated for C₉H₅Cl₂F₃N₂O: 283.97

MS measure: 285, 287 (M+H); 283, 285 (M−H).

[α]_(D) ²⁰=+29; c=0.196 in MeOH.

Example 105(−)-1-(5,6-DiChloro-1H-benzoimidazol-2-yl-)2,2,2-trifluoro-ethanol

A solution of “Peak 2” prepared as in Example 91 (103 mg; 0.21 mmoles)was suspended in a mixture of dioxane and water (10 mL, 4:1) and treatedwith NaOH (0.5 mL; 2 mmoles). The reaction was stirred vigorously andheated to 50′C for 30 min, then cooled to room temperature. The reactionwas diluted with water (50 mL) and 1 N HCl (3 mL, 3 mmol). The resultingwhite precipitate was collected by suction filtration, dissolved inethyl acetate and then purified by flash chromatography (SiO₂, 30% ethylacetate/dcm) to yield the title compound as a white solid.

¹H NMR (400 MHz, CD₃CN) δ 7.80 (s, 2H), δ 5.43 (q, J=6.8 Hz, 1H)

MS calculated for C₉H₅Cl₂F₃N₂O: 283.97

MS measured: 285, 287 (M+H); 283, 285 (M−H).

[α]_(D) ²⁰=−27; c=0.183 in MeOH.

Example 106 5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole

4,5-Dichloro-benzene-1,2-diamine (10.0114 g; 56.5520 mmoles) and3,3,3-trifluoro-propionic acid (7.5 mL; 84.9 mmoles) were combined with6N HCl (20 mL; 120 mmoles) and heated to 108° C. for 18 hrs. Thereaction mixture was cooled to room temperature, diluted with ethylacetate (200 mL) and water (200 mL), then then sodium bicarbonate (15.15g; 180.3 mmoles) was added slowly and in portions to quench thereaction. The aqueous layer was separated and extracted with ethylacetate (3×60 mL). The extracts were combined, washed with water (60 mL)and brine (60 mL), then dried over Na₂SO₄. The filtrate was concentratedin vacuo to yield a crude brown solid. A sample of the crude brown solidwas purified by column chromatography (SiO₂; 100% CH₂Cl₂) to yield thetitle compound as a light brown solid.

¹H NMR (400 MHz, CD₃CN) δ 7.78 (s, 2H), δ 3.87 (q, J=10.7 Hz, 2H)

MS calculated for C₉H₅Cl₂F₃N₂: 267.98

MS measured: 269, 271 (M+H); 267, 269 (M−H).

Example 107 Ventral Prostate and Seminal Vesicle Weight in vivo Assay

Immature (approximately 50 g) castrated male Sprague Dawley rats(Charles River) were treated once daily for five days with test compound(usually given orally at 40 mg/kg in a volume of 0.3 mL, in 30%cyclodextrin or 0.5% methylcellulose vehicle) and with testosteronepropionate (given subcutaneously by injection at the nape of the neck at2 mg/kg, in a volume of 0.1 mL in sesame oil). On the sixth day, therats were euthanized by asphyxiation in carbon dioxide. Ventralprosatates and seminal vesicles were removed and their wet weightsdetermined. Test compound activity was determined as the percentinhibition of testosterone-enhanced tissue weights, with avehicle-treated control group set to zero percent and a testosteronealone-treated control group set to 100%.

Representative compounds of the present invention were tested accordingto the procedure described, with results as listed in Table 7 below. Atest compound is listed as “active” if the non weight adjusted prostateweight was ≦40 mg or the % Inhibition prostate weight, body weightadjusted was ≧40% @ 2 mg/day dosage. ID₅₀'s, if determined, of 15 mg/dayalso indicated an “active” compound. For the compounds listed in Table 7as “inactive”, one skilled in the art will recognize that said compoundsmay or may not have shown an effect on prostate and/or vesical weight,rather they are listed herein as “inactive” as they did not meet thespecified criteria defined above.

TABLE 7 ID No. Activity 1 active 2 active 3 inactive 4 active 5 inactive7 active 8 active 9 active 10 inactive 12 active 13 active 14 active 15active 16 active 17 inactive 18 active 20 inactive 21 active 22 inactive23 active 24 inactive 25 active 26 inactive 27 active 28 active 29active 30 active 31 active 33 active 36 inactive 37 active 38 inactive39 active 40 active 41 active 42 inactive 44 inactive 45 inactive 46inactive 48 active 49 inactive 50 active 51 active 53 inactive 54inactive 55 active 56 inactive 57 active 58 active 59 active 60 inactive61 active 62 active 63 active 64 inactive 65 inactive 66 active 68active 69 inactive 70 inactive 71 active 72 inactive 73 active 74inactive 75 active 76 active 77 inactive 78 active 79 inactive 80 active81 inactive 82 active 83 active 84 inactive 85 inactive 86 inactive 87inactive 88 inactive 89 active 90 inactive 91 active 92 active 93 active94 inactive 95 inactive 96 inactive 97 active 98 active 99 active 100active 101 inactive 102 active 104 inactive 105 active 106 active 107active 108 active 109 active 110 active 111 inactive 112 active 113inactive 114 active 115 active 116 active 117 active 119 active 120active 121 active 123 inactive 124 active 125 active 126 inactive 128inactive 129 inactive 131 inactive 132 inactive 133 active 134 inactive135 inactive 136 active 137 active 138 active 139 active 140 inactive141 active 142 inactive 144 active 146 active 147 active 148 active 149active 150 active 151 active 152 active 153 inactive 154 inactive 155inactive 156 inactive 157 inactive 159 active 160 active

Example 108 Ventral Prostate and Levator ani Weight in vivo Assay

Mature (150 to 200 g) castrated male Sprague Dawley rats (Charles River)were treated once daily for 14 days with test compound (usuallyadministered by oral gavage at up to the desired dosage, up to 30 mg/kgin a volume of 1 mL, in 30% cyclodextrin or 0.5% methylcellulosevehicle), or with testosterone propionate (administered subcutaneouslyby injection at the nape of the neck at 5 mg/kg, in a volume of 0.1 mLin sesame oil), or with vehicle (1 mL of 30% cyclodextrin or 0.5%methylcellulose, given orally). On the fifteenth day, the rats wereeuthanized by asphyxiation in carbon dioxide. Ventral prostates andlevator ani muscles were removed and their wet weights determined.

Test compound activity was determined as the percent stimulation oftissue weight, with the vehicle-treated control group set to zeropercent and the testosterone alone-treated control group set to 100%. Acompound was designated as “active” if it produced greater than or equalto 25% stimulation of levator ani at 30 mg/kg.

Compound #7 was tested according to the above procedure described above,dosing at 30 mg/kg and was measured to be active, according to the abovecriteria.

Example 109

As a specific embodiment of an oral composition, 100 mg of the Compound#7 prepared as in Example 1 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size 0 hardgel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1-15. (canceled)
 16. A method of treating a disorder mediated by anandrogen receptor, in a subject in need thereof comprising administeringto the subject a therapeutically effective amount of a compound offormula (II)

wherein R¹ is selected from the group consisting of hydrogen, C₁₋₄alkyl,—C₁₋₄alkyl-OH, —C₁₋₄alkyl-CN, —C₁₋₄alkyl-NO₂, —C₁₋₄alkyl-N(R^(A)R^(B)),—C₁₋₄alkyl-CO₂H, —(C₁₋₄alkyl)-X—R⁷, —CH₂-aryl and —CH₂-heteroaryl;wherein the aryl or heteroaryl group (on the —CH₂-aryl and—CH₂-heteroaryl group) is optionally substituted with one or moresubstituents independently selected from halogen, C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄alkoxy,—C₁₋₄alkyl-CN, —C₁₋₄alkyl-OH, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S—C₁₋₄alkyl, —S-(halogen substituted C₁₋₄alkyl),—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl, —O-aralkyl, —C(O)O—C₁₋₄alkyl, —CO₂H,—C(O)H, heteroaryl or heterocycloalkyl; wherein R^(A) and R^(B) areindependently selected from hydrogen or C₁₋₄alkyl; alternatively, R^(A)and R^(B) are taken together with the nitrogen atom to which they arebound to form a five to seven membered aromatic, partially unsaturatedor saturated ring structure, optionally containing one to two additionalheteroatoms selected from O, S or N; and wherein the ring structure isoptionally substituted with C₁₋₄alkyl; wherein X is selected from thegroup consisting of —S—, —SO—, SO₂—, —O—SO₂—, —O—, —C(OH)—, —C(═N(OH))—,—C(O)—, —C(O)—O—, —NR^(C)—, —NR^(C)—C(O)—, —C(O)—NR^(C)—, —NR^(C)—SO₂—and —SO₂—NR^(C)—; wherein R^(C) is selected from hydrogen or C₁₋₄alkyl;wherein R⁷ is selected from the group consisting of C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₂₋₄alkenyl, aryl, aralkyl, biphenyl, cycloalkyl,cycloalkyl-(C₁₋₄alkyl)-, heteroaryl, heteroaryl-(C₁₋₄alkyl)-,heterocycloalkyl and heterocycloalkyl-(C₁₋₄alkyl)-; wherein thecycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone oras part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S(O)₀₋₂—(C₁₋₄alkyl), —SO₂—N(R^(D))₂, aryl,heteroaryl or heterocycloalkyl; wherein each R^(D) is independentlyselected from hydrogen or C₁₋₄alkyl; provided that when X is O orNR^(C), then R⁶ is other than C₂₋₄alkenyl; R² is selected from the groupconsisting of hydrogen, halogen, C₁₋₄alkyl, halogen substitutedC₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,—O—C₁₋₄alkyl, —S—C₁₋₄alkyl, —SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl and—NR^(E)—C(O)—C₁₋₄alkyl; wherein R^(E) is selected from hydrogen orC₁₋₄alkyl; R³ is selected from the group consisting of hydrogen,halogen, C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano, nitro, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S—C₁₋₄alkyl,—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl and —NR^(F)—C(O)—C₁₋₄alkyl; wherein R^(F)is selected from hydrogen or C₁₋₄alkyl; provided that at least one of R²or R³ is other than hydrogen; a is an integer from 0 to 1; R¹⁰ isselected from the group consisting of hydrogen, halogen, C₁₋₄alkyl,halogen substituted C₁₋₄alkyl and —O—C(O)—R⁸; wherein R⁸ is selectedfrom the group consisting of C₁₋₄alkyl, cycloalkyl,cycloalkyl-(C₁₋₄alkyl)-, aryl, aralkyl, heteroaryl,heteroaryl-(C₁₋₄alkyl)-, heterocycloalkyl andheterocycloalkyl-(C₁₋₄alkyl)-; wherein the alkyl, cycloalkyl, aryl,heteroaryl or heterocycloalkyl group, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino ordi(C₁₋₄alkyl)amino; R¹¹ is selected from the group consisting ofhydrogen and halogen; alternatively, R¹⁰ and R¹¹ are taken together withthe carbon atom to which they are abound to form —C(O)—, C═N(OH) or—C═N(O—C₁₋₄alkyl); R¹² is selected from the group consisting ofC₁₋₄alkyl, halogen substituted C₁₋₄alkyl, —C₁₋₄alkyl-OH, —C₁₋₄alkyl-CN,—C₁₋₄alkyl-NO₂, —C₁₋₄alkyl-N(R^(G)R^(H)), C₁₋₄alkyl-CO₂H,—(C₁₋₄alkyl)-Y—R⁹, —CH₂-aryl and —CH₂-heteroaryl; wherein the aryl orheteroaryl (on the —CH₂-aryl or —CH₂-heteroaryl group) is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy,halogen substituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S(O)₀₋₂—C₁₋₄alkyl or —SO₂—N(R^(J))₂; wherein eachR^(J) is independently selected from hydrogen or C₁₋₄alkyl; whereinR^(G) and R^(H) are independently selected from hydrogen or C₁₋₄alkyl;alternatively, R^(G) and R^(H) are taken together with the nitrogen atomto which they are bound to form a five to seven membered aromatic,partially unsaturated or saturated ring structure, optionally containingone to two additional heteroatoms selected from O, S or N; and whereinthe ring structure is optionally substituted with C₁₋₄alkyl; wherein Yis selected from the group consisting of —S—, —SO—, SO₂—, —O—SO₂—, —O—,—C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR^(K)—, —NR^(K)—C(O)—,—C(O)—NR^(K), —NR^(K)—SO₂— and —SO₂—NR^(K)—; wherein R^(K) is selectedfrom hydrogen or C₁₋₄alkyl; wherein R⁹ is selected from the groupconsisting of C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₂₋₄alkenyl,aryl, aralkyl, biphenyl, cycloalkyl, cycloalkyl-(C₁₋₄alkyl)-,heteroaryl, heteroaryl-(C₁₋₄alkyl)-, heterocycloalkyl andheterocycloalkyl-(C₁₋₄alkyl)-; wherein the cycloalkyl, aryl, heteroarylor heterocycloalkyl group, whether alone or as part of a substituentgroup is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, carboxy, C₁₋₄alkyl,halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogen substitutedC₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,—S(O)₀₋₂—(C₁₋₄alkyl), —SO₂—N(R^(L))₂ or —NR^(M)—C(O)—C₁₋₄alkyl; whereineach R^(L) is independently selected from hydrogen or C₁₋₄alkyl; andwherein R^(M) is selected from hydrogen or C₁₋₄alkyl; provided that whenY is O or NR^(K), then R⁹ is other than C₂₋₄alkenyl; provided that whenR¹ is —CH₂-phenyl wherein the phenyl is substituted with—C(O)O—C₁₋₄alkyl or —CO₂H; R² is methyl; R³ is methyl; a is 0; R¹⁰ ishydrogen; and R¹¹ is hydrogen; then R¹² is other than —CH₂-phenyl;provided further that when R¹ is —CH₂-phenyl wherein the phenyl issubstituted with —C(O)O—C₁₋₄alkyl or —CO₂H; R² and R³ are selected to be(H and fluoro), (fluoro and H), (methyl, methyl) or (H andtrifluoromethyl); a is an integer form 0 to 1; R¹⁰ is hydrogen; and R¹¹is hydrogen; then R¹² is other than C₁₋₄alkyl; provided further thatwhen R¹ is hydrogen or C₁₋₄alkyl; a is 0; R¹⁰ and R¹¹ are taken togetherwith the carbon atom to which they are abound to form —C(O)—, one of R²or R³ is hydrogen and the other of R² or R³ is selected from halogen,C₁₋₄alkyl, —O—C₁₋₄alkyl or nitro, then R¹² is other than C₁₋₄alkyl,C₁₋₄alkyl substituted with one halogen or benzyl; provided further thatwhen R¹ is —CH₂-phenyl; a is 0; R¹⁰ and R¹¹ are taken together with thecarbon atom to which they are abound to form —C(O)—, of R² is hydrogen;and R³ is nitro, then R¹² is other than C₁₋₄alkyl; provided further thatwhen R¹ is hydrogen; a is 0; R² is —O—C₁₋₄alkyl, R³ is —O—C₁₋₄alkyl; andR¹⁰ and R¹¹ are taken together with the carbon atom to which they areabound to form —C(O)—; then R¹² is other than benzyl; provided furtherthat when R¹ is —C₁₋₄alkyl-N(C₁₋₄alkyl)₂; a is 0; R² is —O—C₁₋₄alkyl; R³is —O—C₁₋₄alkyl; and R¹⁰ and R¹¹ are taken together with the carbon atomto which they are abound to form —C(O)—, then R¹² is other than benzyl,wherein the benzyl is substituted with a halogen; or a pharmaceuticallyacceptable salt thereof.
 17. A method of treating a disorder mediated byan androgen receptor, in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of thepharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of formula (II)

wherein R¹ is selected from the group consisting of hydrogen, C₁₋₄alkyl,—C₁₋₄alkyl-OH, —C₁₋₄alkyl-CN, —C₁₋₄alkyl-NO₂, —C₁₋₄alkyl-N(R^(A)R^(B)),—C₁₋₄alkyl-CO₂H, —(C₁₋₄alkyl)-X—R⁷, —CH₂-aryl and —CH₂-heteroaryl;wherein the aryl or heteroaryl group (on the —CH₂-aryl and—CH₂-heteroaryl group) is optionally substituted with one or moresubstituents independently selected from halogen, C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₁₋₄alkoxy, halogen substituted C₁₋₄ alkoxy,—C₁₋₄alkyl-CN, —C₁₋₄alkyl-OH, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S—C₁₋₄alkyl, —S-(halogen substituted C₁₋₄alkyl),—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl, —O-aralkyl, —C(O)O—C₁₋₄alkyl, —CO₂H,—C(O)H, heteroaryl or heterocycloalkyl; wherein R^(A) and R^(B) areindependently selected from hydrogen or C₁₋₄alkyl; alternatively, R^(A)and R^(B) are taken together with the nitrogen atom to which they arebound to form a five to seven membered aromatic, partially unsaturatedor saturated ring structure, optionally containing one to two additionalheteroatoms selected from O, S or N; and wherein the ring structure isoptionally substituted with C₁₋₄alkyl; wherein X is selected from thegroup consisting of —S—, —SO—, SO₂—, —O—SO₂₋₅—O—, —C(OH)—, —C(═N(OH))—,—C(O)—, —C(O)—O—, —NR^(C)—, —NR^(C)—C(O)—, —C(O)—NR^(C)—, —NR^(C)—SO₂—and —SO₂—NR^(C)—; wherein R^(C) is selected from hydrogen or C₁₋₄alkyl;wherein R⁷ is selected from the group consisting of C₁₋₄alkyl, halogensubstituted C₁₋₄alkyl, C₂₋₄alkenyl, aryl, aralkyl, biphenyl, cycloalkyl,cycloalkyl-(C₁₋₄alkyl)-, heteroaryl, heteroaryl-(C₁₋₄alkyl)-,heterocycloalkyl and heterocycloalkyl-(C₁₋₄alkyl)-; wherein thecycloalkyl, aryl, heteroaryl or heterocycloalkyl group, whether alone oras part of a substituent group is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄ alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S(O)₀₋₂—(C₁₋₄alkyl), —SO₂—N(R^(D))₂, aryl,heteroaryl or heterocycloalkyl; wherein each R^(D) is independentlyselected from hydrogen or C₁₋₄alkyl; provided that when X is O orNR^(C), then R⁶ is other than C₂₋₄alkenyl; R² is selected from the groupconsisting of hydrogen, halogen, C₁₋₄alkyl, halogen substitutedC₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,—O—C₁₋₄alkyl, —S—C₁₋₄alkyl, —SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl and—NR^(E)—C(O)—C₁₋₄alkyl; wherein R^(E) is selected from hydrogen orC₁₋₄alkyl; R³ is selected from the group consisting of hydrogen,halogen, C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, cyano, nitro, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S—C₁₋₄alkyl,—SO—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl and —NR^(F)—C(O)—C₁₋₄alkyl; wherein R^(F)is selected from hydrogen or C₁₋₄alkyl; provided that at least one of R²or R³ is other than hydrogen; a is an integer from 0 to 1; R¹⁰ isselected from the group consisting of hydrogen, halogen, C₁₋₄alkyl,halogen substituted C₁₋₄alkyl and —O—C(O)—R⁸; wherein R⁸ is selectedfrom the group consisting of C₁₋₄alkyl, cycloalkyl,cycloalkyl-(C₁₋₄alkyl)-, aryl, aralkyl, heteroaryl,heteroaryl-(C₁₋₄alkyl)-, heterocycloalkyl andheterocycloalkyl-(C₁₋₄alkyl)-; wherein the alkyl, cycloalkyl, aryl,heteroaryl or heterocycloalkyl group, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogensubstituted C₁₋₄ alkoxy, cyano, nitro, amino, C₁₋₄alkylamino ordi(C₁₋₄alkyl)amino; R¹¹ is selected from the group consisting ofhydrogen and halogen; alternatively, R¹⁰ and R¹¹ are taken together withthe carbon atom to which they are abound to form —C(O)—, C═N(OH) or—C═N(O—C₁₋₄alkyl); R¹² is selected from the group consisting ofC₁₋₄alkyl, halogen substituted C₁₋₄alkyl, —C₁₋₄alkyl-OH, —C₁₋₄alkyl-CN,—C₁₋₄alkyl-NO₂, —C₁₋₄alkyl-N(R^(G)R^(H)), C₁₋₄alkyl-CO₂H,—(C₁₋₄alkyl)-Y—R⁹, —CH₂-aryl and —CH₂-heteroaryl; wherein the aryl orheteroaryl (on the —CH₂-aryl or —CH₂-heteroaryl group) is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy,halogen substituted C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —S(O)₀₋₂—C₁₋₄alkyl or —SO₂—N(R^(J))₂; wherein eachR^(J) is independently selected from hydrogen or C₁₋₄alkyl; whereinR^(G) and R^(H) are independently selected from hydrogen or C₁₋₄alkyl;alternatively, R^(G) and R^(H) are taken together with the nitrogen atomto which they are bound to form a five to seven membered aromatic,partially unsaturated or saturated ring structure, optionally containingone to two additional heteroatoms selected from O, S or N; and whereinthe ring structure is optionally substituted with C₁₋₄alkyl; wherein Yis selected from the group consisting of —S—, —SO—, SO₂—, —O—SO₂—, —O—,—C(OH)—, —C(═N(OH))—, —C(O)—, —C(O)—O—, —NR^(K)—, —NR^(K)—C(O)—,—C(O)—NR^(K)—, —NR^(K)—SO₂— and —SO₂—NR^(K)—; wherein R^(K) is selectedfrom hydrogen or C₁₋₄alkyl; wherein R⁹ is selected from the groupconsisting of C₁₋₄alkyl, halogen substituted C₁₋₄alkyl, C₂₋₄alkenyl,aryl, aralkyl, biphenyl, cycloalkyl, cycloalkyl-(C₁₋₄alkyl)-,heteroaryl, heteroaryl-(C₁₋₄alkyl)-, heterocycloalkyl andheterocycloalkyl-(C₁₋₄alkyl)-; wherein the cycloalkyl, aryl, heteroarylor heterocycloalkyl group, whether alone or as part of a substituentgroup is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, carboxy, C₁₋₄alkyl,halogen substituted C₁₋₄alkyl, C₁₋₄alkoxy, halogen substitutedC₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,—S(O)₀₋₂—(C₁₋₄alkyl), —SO₂—N(R^(L))₂ or —NR^(M)—C(O)—C₁₋₄alkyl; whereineach R^(L) is independently selected from hydrogen or C₁₋₄alkyl; andwherein R^(M) is selected from hydrogen or C₁₋₄alkyl; provided that whenY is O or NR^(K), then R⁹ is other than C₂₋₄alkenyl; provided that whenR¹ is —CH₂-phenyl wherein the phenyl is substituted with—C(O)O—C₁₋₄alkyl or —CO₂H; R² is methyl; R³ is methyl; a is 0; R¹⁰ ishydrogen; and R¹¹ is hydrogen; then R¹² is other than —CH₂-phenyl;provided further that when R¹ is —CH₂-phenyl wherein the phenyl issubstituted with —C(O)O—C₁₋₄alkyl or —CO₂H; R² and R³ are selected to be(H and fluoro), (fluoro and H), (methyl, methyl) or (H andtrifluoromethyl); a is an integer form 0 to 1; R¹⁰ is hydrogen; and R¹¹is hydrogen; then R¹² is other than C₁₋₄alkyl; provided further thatwhen R¹ is hydrogen or C₁₋₄alkyl; a is 0; R¹⁰ and R¹¹ are taken togetherwith the carbon atom to which they are abound to form —C(O)—, one of R²or R³ is hydrogen and the other of R² or R³ is selected from halogen,C₁₋₄alkyl, —O—C₁₋₄alkyl or nitro, then R¹² is other than C₁₋₄alkyl,C₁₋₄alkyl substituted with one halogen or benzyl; provided further thatwhen R¹ is —CH₂-phenyl; a is 0; R¹⁰ and R¹¹ are taken together with thecarbon atom to which they are abound to form —C(O)—, of R² is hydrogen;and R³ is nitro, then R¹² is other than C₁₋₄alkyl; provided further thatwhen R¹ is hydrogen; a is 0; R² is —O—C₁₋₄alkyl, R³ is —O—C₁₋₄alkyl; andR¹⁰ and R¹¹ are taken together with the carbon atom to which they areabound to form —C(O)—; then R¹² is other than benzyl; provided furtherthat when R¹ is —C₁₋₄alkyl-N(C₁₋₄alkyl)₂; a is 0; R² is —O—C₁₋₄alkyl; R³is —O—C₁₋₄alkyl; and R¹⁰ and R¹¹ are taken together with the carbon atomto which they are abound to form —C(O)—, then R¹² is other than benzyl,wherein the benzyl is substituted with a halogen; or a pharmaceuticallyacceptable salt thereof.
 18. A method of treating a condition selectedfrom the group consisting of prostate carcinoma, benign prostatichyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer,acne, AIDS, cachexia, male contraception, and male performance, in asubject in need thereof comprising administering to the subject atherapeutically effective amount of the compound of claim
 16. 19. Theuse of a compound as in claim 16 for the preparation of a medicament fortreating: (a) prostate carcinoma, (b) benign prostatic hyperplasia, (c)hirsutism, (d) alopecia, (e) anorexia nervosa, (f) breast cancer, (g)acne, (h) AIDS, (i) cachexia, for (j) male contraception, or for (k)male performance enhancement, in a subject in need thereof.